אוסף התקצירים 2017
1University of Haifa, Department of Psychology; 2Ariel University, Department of Behavioral Sciences;
Loneliness is the subjective experience of weak social relations and connectedness that is associated with psychopathology including depression and anxiety. Loneliness is thought to trigger affiliative behaviors on one hand, and hypervigilance to social threat on the other hand. Considering that interpersonal space (IS) serves as an important nonverbal cue that defines social dynamics, in the current study we sought to examine social approach in lonely individuals with a task that measures IS during social interactions in groups. We recruited 112 participants divided into groups of four, who played a computerized paradigm that allows assessing IS during free movement. In the task, different color circles are assigned to four players, who are instructed to move freely. Participants played with friends and strangers and we measured the average distance between each two players throughout the game. Results indicated that lonely individuals kept a larger distance from strangers with no difference in distance kept from friends, compared to non-lonely individuals. These findings suggest that interpersonal distance may play a key role in the perpetuation of loneliness by impairing the formation of new relationships. This merits further investigation into the ways that can be used to relieve loneliness by targeting interpersonal space regulation.
1Beer Yaakov mental Health Center, Faculty of medicine, Tel Aviv university;
Background: Repetitive deep transcranial magnetic stimulation (rdTMS) is efficacious for treatment resistant major depressive disorder (TRD). The efficacy of rdTMS may be optimized by stimulation of both the right and left dorsolateral prefrontal cortex (DLPFC). This study is testing the treatment efficacy in TRD of a novel dual channel rdTMS stimulator that was developed for this purpose. Methods: For this open study we recruited 38 outpatients diagnosed with TRD ranging from 18-65 years of age and rated on the HDRS-21≥25., Twenty seven participants completed all study requirements. The rdTMS dual channel stimulator is the Brainsway Multiway deep TMS device: Two channels: a. 10 Hz over the left PFC. b. 1 Hz over the right PFC. Each patient received 20 treatment sessions, five times a week for 4 consecutive weeks. Primary and secondary efficacy outcome measures were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively Results: HDRS-21 score decreased from an average of 27.22 to 14.22 (P<0.001). Twenty-seven patients completed 4 weeks of treatment. Of them, 13 (48%) showed treatment response (indicating their HDRS-21 score has decreased over 50% from their initial score) and six (22%) showed remission (indicating an HDRS-21 score of less than 10 at the end of the study). Discussion: This open study shows promising results for bilateral simultaneous rdTMS treatment of TRD using a dual channel stimulator. Further randomized controlled studies are necessary for verifying this treatment’s efficacy.
1Dept. of Clinical Biochemistry and Pharmacology and Psychiatry Research Unit, Ben-Gurion University of the Negev, Israel; 2School of Behavioral Sciences, Tel Aviv-Yaffo Academic College, Israel;
Despite the high prevalence~) 1% of the adult population) of bipolar-disorder its pathophysiology or the mechanism by which effective medications exert their therapeutic effect has not yet been unraveled but data from other groups and ours indicate brain mitochondrial dysfunction in the patients and beneficial effects of mood stabilizers (anti-bipolar drugs) on mitochondrial function. We therefore aim to model mild mitochondrial dysfunction in mice using the OxPhos complex I inhibitor rotenone to induce affective-like behavior. Adult ICR mice were treated daily with 0.25 and 0.5 mg/kg/day for four weeks and with 0.75 mg/kg/day for four, six and eight weeks following which the mice were subjected to a battery of behavioral tests [open field, elevated plus maze (EPM), sweet-solution (saccharin) preference, rotarod, forced-swim test (FST) and amphetamine-induced hyperactivity]. Chronic administration of all rotenone doses for four weeks did not affect spontaneous activity or time spent in the center of the open field, sweet-solution preference or behavior in the EPM. 0.5 mg/kg/day for four weeks induced a trend for attenuation of amphetamine-induced hyperactivity. 0.75 mg/kg/day for four or six weeks reduced the immobility time in the FST while eight weeks of treatment significantly increased the immobility time. In conclusion, 0.25 to 0.75 mg/kg/day rotenone for four weeks does not affect basal locomotor activity and anxiety-related behaviors. Interestingly, the effect of 0.75 mg/kg/day on depressive-like behavior in the FST showed dichotomy. Namely, it induced an antidepressant-like phenotype following up to six weeks of treatment but a depressive-like effect following eight weeks. More administration regimens will be tested to substantiate the dichotomous response and to model mild mitochondrial dysfunction.
1Psychology Department, Bar-Ilan University, Ramat Gan, Israel. ; 2Gonda Brain Research Center, Bar-Ilan University, Ramat Gan, Israel.; 3Institute for Drug Research, Medical Faculty, Hebrew University, Jerusalem, 91120, Israel.; 4Geha Mental Health Center, Petah Tiqva, Israel.; 5Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;
Major depressive disorder is a leading cause of disability worldwide; hence, it is necessary to find an appropriate medication. Cannabidiol (CBD), the key non-psychoactive component of the sativa plant, that does not cause negative symptoms, has been shown to have anxiolytic effects, and in a few papers also antidepressive effects. Recently, we showed that oral 30 mg/kg CBD had a pro-hedonic effect on the saccharin preference test. Another compound, CBD acid-methyl ester (CBDA-ME), has been suggested to have more potent effects, but has not been behaviorally tested. Whether administered chronically or after brief sub-chronic administration, antidepressant drugs typically decrease the duration of immobility in the Forced Swim Test (FST). Using the FST, we first examined the effect of orally administered 30 mg/kg CBD in adult male rats from the Wistar-Kyoto (WKY) strain, a genetic animal model of depression. Next, we examined the effect of lower doses of CBDA-ME (0, 0.1, 1, 5 mg/kg). Their control strain was Wistar rats. CBD decreased time floating (immobility) and increased time swimming. Furthermore, 1 mg/kg of CBDA-ME induced the same pattern of effects. In order to explore the effect of CBDA-ME on anhedonia-like behavior we used the saccharin preference test (SPT). As hypothesized, WKY rats showed increased intake of the sweet solution in the SPT after oral administration of 0.1 of CBDA-ME. This provided support for a pro–hedonic effect of CBDA-ME on anhedonia-like behavior, a characteristic of depression as well as of many other mental illnesses. These results provide support for positive effects of acute oral administration of CBD and of much lower doses of CBDA-ME, suggesting therapeutic promise while avoiding potential side effects.
1Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.; 2Geha Mental Health Center, Petach-Tikva, Israel. ; 3Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Petach-Tikva, Israel.;
Objectives: The wide use of antidepressants (ADs) in bipolar disorder I (BD-I) depression is inconsistent with the weak evidence for their effectiveness and safety in this state. Furthermore, there is a paucity of studies on the risk-benefit ratio of AD maintenance treatment in BD-I. We compared the 6-months and 1-year rehospitalization rates of patients with BD-I depression who were discharged with mood stabilizers (MS) or atypical antipsychotics (AAP) with or without AD. Methods: A total of 98 patients with BD-I who were hospitalized with depressive episodes between 2005 and 2013 were retrospectively followed for 6-months and 1-year rehospitalization rates according to treatment at discharge: MS/AAP with or without AD. Durations to rehospitalization were compared between treatment groups. Multivariable survival analyses adjusted for covariates known to influence rehospitalization were conducted. Results: Six-months and 1-year rehospitalization rates were significantly lower in the adjunctive-AD treatment group compared to the no-AD group (9.2% vs. 36.4%, P=.001 and 12.3% vs. 42.4%, P=.001, respectively). Durations to rehospitalization within 6-months and 1-year were significantly longer in the adjunctive-AD treatment group (169.9 vs 141 days, P=.001 and 335.6 vs 252.3 days, P=.001, respectively). Adjunctive-AD treatment at discharge reduced significantly the adjusted risk of rehospitalization within 6-months (HR=0.081, 95% CI: 0.016-0.412, P=.002) and 1-year (HR=0.149, 95% CI: 0.041-0.536, P=.004). Moreover, adjunctive-AD treatment, while reducing adjusted rehospitalization risk for depressive episode did not increase manic episode rehospitalization rates. Conclusions: Adjunctive-AD therapy to MS/AAP may be more effective than MS/AAP monotherapy in preventing rehospitalization during the 1-year period after BD-I depression.
1Psychology Department, Bar-Ilan University, Ramat Gan, Israel.; 2Gonda Brain Research Center, Bar-Ilan University, Ramat Gan, Israel; 3Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel; 4Institute for Drug Research, Medical Faculty, Hebrew University, Jerusalem, 91120, Israel; 5Geha Mental Health Center, Petah Tiqva, Israel; 6Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 7;
The underlying pathophysiology of major depressive disorder is diverse, yet treatment strategies remain limited. There is a need for alternative drug therapies to combat the debilitating symptoms of the disorder. The endocannabinoid system has been linked to depression in clinical and pre-clinical studies. The exogenous cannabinoid Cannabidiol (CBD) is the major non-psychomimetic phytocannabinoid compound in the plant Cannabis Sativa. Accumulating evidence suggests that CBD may be an effective and safe anxiolytic and antidepressant agent. Another related compound, Cannabidiolic acid-methyl ester (HU-580) demonstrated more potent effects in vitro, however, has undergone only minimal behaviorally assessment. We explore the properties of CBD and HU-580 using two “depressive-like” genetic rat models; the Wistar-Kyoto (WKY) and the Flinder’s Sensitive Line (FSL) which both present many behavioral and physiological endophenotypes frequently observed in major depression. In the first study, male and female WKY and FSL rats underwent Forced swim test (FST) followed by a saccharin preference test (SPT) after oral administration of 30 mg/kg of CBD. In the second study, FST was conducted after oral administration of HU-580 (0.1, 1, 5 mg/kg). The results indicate that there is a pro-hedonic effect of CBD in both male (previous study) and female (current study) WKY rats at 30 mg/kg as demonstrated by the SPT (p<0.05), but CBD did not change the saccharin preference of FSL rats. In addition, males of both strains and female WKY rats displayed reduced immobility in the FST when treated with CBD (p<0.05) and that the same pattern were observed with male WKY and FSL rats with 1 mg/kg of HU-580 (p<0.05). These findings extend the limited knowledge on the antidepressant effects of CBD and HU-580, suggesting that they may be beneficial for the treatment of clinical depression and other states with prominent symptoms of helplessness and anhedonia.
11Ariel University, Ariel 40700, Israel.; 2;
Background Depression is a psychiatric disorder common in patients with cancer and associated with tumor development and progression. Cellular adhesion integrin αvβ3 plays a critical role in tumorigenesis and neoplastic progression. It has been recently shown that integrin αvβ3 is presented on serotonergic neurons and was suggested to be involved in the regulation of serotonergic neurotransmission and mechanism of antidepressant action. We discovered a 9-amino acid cyclic peptide (ALOS4) with specific binding properties towards αvβ3 and potent anticancer activity. The aim of this study was to evaluate the anti-depressive and anxiolytic properties of ALOS4 using selectively bred submissive mice with strong depressive-like behavior. Results Submissive mice were treated with acute (10mg/kg, 30mg/kg, 90mg/kg single i.v. injection) and sub-chronic (10mg/kg, 30mg/kg, 90mg/kg each two days i.v. injection, for 10 days) doses of ALOS4. We found that either acute or sub-chronic ALOS4 administration dose-dependently increased exploratory activity of submissive mice in the Open field test. Mice treated sub-chronically exhibited significant reduction of anxiety-like behavior in Elevated Plus Maze test. Depressive-like behavior measured by the Forced Swim test showed a significant reduction in both treatment regimes. In addition, , the fat pad mass of mice treated with ALOS4 showed a tendency to increase. Conclusions Our findings provide evidence of anti-depressive and anxiolytic properties of ALOS4. We anticipate that these effects were achieved via αvβ3 signaling pathways that will be further elucidated. We convinced that in addition to its previously established anticancer properties and in accordance to anti-depressive results represented in this study, ALOS4 may be considered as a potential psychotropic drug candidate, especially for the cancer patients who suffer from anxiety and depression.
1Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel;
Despite established efficacy against mood episodes and proven ability to reduce suicide in bipolar (BP) patients, lithium (Li) therapy has side effects of which most troublesome is chronic kidney disease (CKD). It is, thus, imperative to search new strategies to reduce Li's toxicity without conceding its therapeutic advantages. Inflammation plays a role in the pathophysiology and treatment of BP disorder. Aspirin (ASA) is a non-steroidal anti-inflammatory drug (NSAID) administered widely at a low-dose as prophylactic treatment against thrombotic events in coronary artery disease. There is circumstantial evidence that ASA+Li co-administration may enhance Li's therapeutic efficacy without aggravating its toxicity, but the mechanism is unknown, and it is not understood why, unlike other NSAIDs, ASA does not aggravate Li's toxicity. We hypothesize that chronic administration of low-dose ASA with low to medium doses of Li will attenuate Li-induced nephrotoxicity with no lessened efficacy. Our objectives are: 1) Titrate Li doses to reach blood levels of 0.2-0.4 meq/L, 0.4-0.6 meq/L and 0.8-1.0 meq/L. To this end rats were administered 0.05, 0.1, 0.15 and 0.2% LiCl in food and their blood Li levels monitored at 2, 4 and 6 weeks of treatment. 2) Examine the safety of chronic ASA+Li. To this end we monitored blood creatinine levels, water consumption and urinary output (determinants of renal function). 3) Test behavioral effects of chronic ASA+Li treatment in mania- and depression-like behavioral models. We used the amphetamine-induced hyperlocomotion test (manic-like behavior). Preliminary results: 1) The desired blood Li levels were obtained following 4 weeks of treatment. We are currently trying higher doses to reach the goal levels following 2 weeks. 2) Low-dose ASA add-on to Li was safe and did not alter serum Li levels. 3) Low-dose ASA+Li led to significantly decreased water consumption and urinary output compared to Li only. 4) Low-dose ASA enhanced the anti-manic-like effect of low-dose Li. We expect that successful completion of the study will uncover if and shed light on the mechanism by which aspirin augments Li's efficacy. It will also provide data regarding the safety/toxicity of ASA-Li co-administration.
1School of Behavioral Sciences, Tel Aviv-Yaffo Academic College; 2Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev; 3College of Pharmacy, University of Minnesota;
Background: Autophagy, a cell survival promoting process, was recently suggested to be involved in the therapeutic action of antidepressant and mood stabilizing drugs. Previous data from our lab demonstrated that repeated administration of compounds that enhance autophagy via different pathways, including rapamycin and trehalose result in antidepressant-like effects and in changes in autophagy-related protein in the frontal cortex of mice. To further understand possible implications of autophagy manipulations in bipolar disorder and its treatment we examined the effects of rapamycin in a strain specific model of mania and examined the behavioral consequences of a conditional deletion of Atg5, a gene required for autophagy in mice. Methods: For the pharmacological study we administered sub-chronic doses of rapamycin to black Swiss mice and tested them behaviorally. For the molecular study we created a conditional knockout mouse model by crossing Atg5flox/flox mice with a mouse strain carrying Cre recombinase under the control of the CamK2a promoter. Atg5 gene deletion was induced by tamoxifen treatment in 6 week old mice. Two or four weeks after treatment mice were examined in a battery of behavioral tests related to basic neuromotor measures and to affective-like change. Results: (1) rapamycin induced antimanic like effects. (2) Conditional KO of Atg5 had no effects on basic neuromotor measures but had a time after induction-dependent effect to induce manic-like behavior in the sweet solution preference test, the forced swim test, the tail suspension test and the amphetamine-induced hyperactivity test. Discussion: These results further support the relationship between autophagy and affective disorders and the possibility that autophagy enhancement could provide a novel target for the development of mood stabilizing drugs.
1University of haifa;
Early life adverse experiences such as abuse or maltreatment significantly increase predisposition to psychopathologies, including depression and anxiety. The endocannabinoid system has been suggested as a therapeutic target for the treatment of stress- and anxiety-related disorders. Study in our lab showed that chronic cannabinoids during "late adolescence" (extensive cannabis use in humans at the ages 18-25) can reverse the long-term adverse effects of early stress (ES) on neurocognitive and emotional function in adulthood. However, human and animal studies provide evidence for vulnerable periods of brain development for deleterious effects of cannabinoids, such as adolescence. Here we examined whether cannabinoids administered during mid-adolescence and post-adolescence could exacerbate or reverse the long-term adverse effects of ES on emotional function in adulthood. Male and female rats were exposed to early maltreatment stress from postnatal day (P) 7 to P14. During P30 to P45 (i.e., mid- adolescence) or during P45-P60 (i.e., post- adolescence) endocannabinoid signaling was enhanced; rats received chronic treatment with the FAAH inhibitor URB597 (URB). On P85 (i.e., adulthood) rats were taken to test for emotional function (i.e., depression-like symptoms). ES male and female rats demonstrated depression-like behavior at adulthood such as reduced social behavior and increased despair. Enhancing endocannabinoid signaling during adolescence exacerbated the protracted effects of ES exposure. However, when endocannabinoid signaling was enhanced during post-adolescence (P45-60), the long-term aversive effects of ES exposure were prevented. Our findings suggest that adolescence period represents a vulnerable time period for persistent adverse effects of cannabinoids whereas the post-adolescence period can provide a possible neurodevelopment window for chronic treatment with cannabinoids.
1Department of Psychology, University of Haifa; 2Department of Neurobiology, University of Haifa;
Over half of all patients who suffer from neuropathic pain develop mood disorders such as depression and anxiety but the mechanisms underlying this comorbidity are not fully understood. Nowadays, there is growing evidence for the efficiency of the use of cannabis in alleviating symptoms of both depression and chronic pain. In this study we examined the emotional component of neuropathic pain. Rats with sciatic nerve ligation (SNL) model of neuropathic pain (NP) were chronically adminsitered with vehicle or the endocannabinoid agonist URB597 for two weeks and tested for depressive-like symptoms and performance in appetative and aversive memory tasks. We found that compared to controls, NP rats showed reduced preference to saccharin (i.e., anhedonia), increased learned helplesness, hypolocomotion and impaired performance in the appetative and aversive memory tasks. The cannabinoid agonist URB597ameliotaed the NP induced depression-like symptoms and the impaired perfromance in the aversive memory task, but not in the appetative memory task. URB597 had no effect on pain levels as measured by the Von Frey test.These results indicate that neuropathic pain can induce depressive-like behavior, which can be alleviated by the use of the cannabinoid agonist URB597. This suggests that the endocannabinoid system is implicated in the emotional component of neuropathic pain.
1Prof Irit Akirav;
Chronic direct activation of cannabinoid receptors may lead to downregulation of CB1 receptors which may in turn result in a depression-like phenotype in certain individuals and increase risk of addiction. We examined the effects of chronic cannabinoid receptor activation before exposure to a traumatic event on the expression of CB1 reeptors (CB1r) in the basolateral amygdala (BLA) and CA1 and on post-stress protracted symptoms. Chronic treatment with the CB1/2 receptor agonist WIN55,212-2 (WIN; 1.2 mg/kg, i.p.) before trauma exposure had differential effects on depression- and anxiety-like behavioral measures depending on withdrawal periods. In the 24 hrs withdrawal condition, WIN enhanced fear retrieval and impaired extinction, increased anhedonia and despair, but had a therapeutic effect in the startle test. In the 10 days withdrawal condition, WIN enhanced fear retrieval and impaired extinction without preventing the stress-induced negative effects of the shock on anhedonia or startle response, but had a therapeutic effect in the despair test. Chronic treatment with WIN55,212-2 was found to down regulate CB1r protein levels in the BLA in the 10 days withdrawal condition, and to upregulate CB1r protein levels in the 24 hrs condition. In the CA1, rats chronically injected with vehicle or WIN demonstrated downregulation of CB1r protein levels. Pre-trauma exposure to cannabinoids may have deleterious effects on emotional function suggesting that chronic pre exposure to direct CB1/2 receptor agonist may not be an optimal way to manipulate the endocannabinoid system in stressful individuals.
1Department of Psychology, University of Haifa, Haifa, Israel; 2The Integrated Brain and Behavior Research Center (IBBR), University of Haifa, Haifa, Israel; 3Department of Psychiatry and Behavioral Sciences, Stanford University, California, USA; 4Sierra-Pacific Mental Illness Research, Education, and Clinical Center Veterans Affairs Palo Alto Health Care System;
Evidence suggests that abnormal cognitive and affective processes play a causal role in the development of depression. Nevertheless, studies demonstrated that cognitive and affective neurobehavioral functions are plastic and may change following learning experiences. Cognitive training, a relatively new intervention which targets the biological mechanisms underlying different psychopathologies, was shown to be effective in reducing depressive symptoms. The current study is a randomized control trial designated to evaluate the efficacy of an affective-cognitive comprehensive training intervention, at alleviating depression symptoms. All phases of the study were delivered in a computerized and web-based manner, in order to reach a variety of participants (with no geographical dependency) and a large sample size (N=167), in a cost-effective manner. Cognitive-affective training alleviated depressive symptoms and improved cognitive functions. However, cognitive-affective training effect was only modest compared to the control training. No moderation effect was found to anxiety levels at baseline. Notwithstanding, dropout rates were very high (47.9%) and not equivalent between the groups. Although we could not attribute these differences to demographic characteristics or symptom severity we believe the missing at random assumption is questionable and one must consider results very carefully. These outcomes demonstrate the complexity of the cognitive training intervention. Like every other intervention – rigorous adherence and follow up processes are crucial in achieving therapeutic benefits. Therefore, optional dropout causes and future recommendations will be presented.
1School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel; 4School of Behavioral Science, the Academic College of Tel-Aviv Yaffo, Israel; 5Department of Education and Psychology, the Open University, Raanana, Israel;
The comorbidity between cancer and depression is well noted, with cancer patients often suffering from fear, anxiety, and depression. Selective serotonin reuptake inhibitors (SSRIs) are a common first line treatment for anxiety and depression, but it is unclear whether and in what manner SSRIs affect cancer progression and metastasis, which are the main causes of cancer-related mortality. In this study, we employed two tumor models to study the effect of escitalopram on primary tumor growth and metastasis development, mimicking clinical use of SSRIs in the context of cancer. In the first model, C57BL/6j mice underwent intra-pancreatic injection of luciferase-labeled Panc02 tumor cells, to establish orthotopic primary tumors, and one week later received daily treatment with either vehicle or 15mg/kg escitalopram until sacrifice. This experiment was performed twice, using two different drug administration techniques, a daily intraperitoneal (IP) injection (n=21), or IP-implanted Alzet osmotic pumps (0.11µl/hr for 28 days; n=28). Bioluminescence imaging was conducted weekly to assess tumor size. In the second tumor model, 28 F344 rats were implanted with 28-day Alzet osmotic pumps (2.5µl/hr) one week before intravenous (IV) injection of MADB106 mammary adenocarcinoma cells. Three weeks following tumor injection, lungs were harvested and metastases enumerated. Surprisingly, escitalopram accelerated the growth of Panc02 tumors (p=0.0531 and p=0.0488 for injection or pump techniques, respectively), and significantly increased the number of MADB106 lung metastases (p=0.04377). These findings demonstrate deleterious effects of escitalopram on cancer progression, and indicate a necessity to reconsider its clinical use in the perioperative context of cancer treatment. Furthermore, a third tumor model is in progress to examine the deleterious effects of stress and of six-week escitalopram on establishment and growth of luciferase-labeled colorectal (CT26) liver metastases.
1Department of Psychology, University of Haifa; 2Department of Neurobiology, University of Haifa;
Over half of all patients who suffer from neuropathic pain develop mood disorders such as depression and anxiety but the mechanisms underlying this comorbidity are not fully understood. Nowadays, there is growing evidence for the efficiency of the use of cannabis in alleviating symptoms of both depression and chronic pain. In this study we examined the emotional component of neuropathic pain. Rats with sciatic nerve ligation (SNL) model of neuropathic pain (NP) were chronically adminsitered with vehicle or the endocannabinoid agonist URB597 for two weeks and tested for depressive-like symptoms and performance in appetative and aversive memory tasks. We found that compared to controls, NP rats showed reduced preference to saccharin (i.e., anhedonia), increased learned helplesness, hypolocomotion and impaired performance in the appetative and aversive memory tasks. The cannabinoid agonist URB597 ameliotaed the NP induced depression-like symptoms and the impaired perfromance in the aversive memory task, but not in the appetative memory task. URB597 had no effect on pain levels as measured by the Von Frey test. These results indicate that neuropathic pain can induce depressive-like behavior, which can be alleviated by the use of the cannabinoid agonist URB597. This suggests that the endocannabinoid system is implicated in the emotional component of neuropathic pain.
1School of Behavioral Sciences, Tel Aviv-Yaffo Academic College; 2Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev; 3Dept. of Psychology, Ben-Gurion University of the Negev; 4Dept. of Psychiatry, Haim Sheba Medical Center;
Significant clinical data suggest that the polarity of episodes of bipolar patients, over the course of the disorder, as well as the polarity of initial or index episode may be strong predictors of recurrence to a specific episode. Around one-half of patients were reported to present predominant polarity and a number of studies demonstrated clinical differences between predominantly manic and predominantly depressed patients. Thus, at the clinical level, predominant polarity should be taken into account when deciding on maintenance therapy of bipolar disorder. In that context, important work was invested to develop a polarity index measure for drugs that can assist clinicians in selecting the most appropriate treatment for patients. However, the underlying biology of predominant polarity had not been studied yet. One way to begin such studies is to utilize animal models but there are no available models for predominant polarity. The current study was designed in an attempt to develop such model. Specifically, the most frequently used screening model for mania-like behavior is amphetamine-induced hyperactivity (AIH) whereas the most frequently used screening model for depression-like behavior is the forced swim test (FST). In the current study we will repeatedly treat a cohort of mice with amphetamine and measure their response. Mice will then be withdrawn from amphetamine, a procedure known to induce depression-like behavior. Mice will then be tested in the FST. If indeed mice show predominant polarity, we expect that the most active mice in the AIH (manic-like) will be also the most active in the FST (least depression-like) and vice versa therefore identification of discrete more manic-like versus more depression-like sub-groups. If that will be the case it will be possible to examine biological differences between these groups at levels and detail that are impossible in human studies
1Biological Psychiatry Laboratory, Hadassah - Hebrew University Medical Center, Jerusalem, Israel; 2Functional Genomics Laboratory, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel ;
Chronic stress (CS) plays a key role in neuropsychiatric disorders of the elderly. However, the biological pathways involved, including the role of miRNAs, are poorly understood. The present study was designed to test the hypothesis that CS induces differential cognitive-behavioral effects and expression patterns of MiRNAs in young adult and old mice. Young adult (3 month) and old (21 month) female RCC-C57BL/6 mice (n=80) were exposed to either CS or control condition for 9 weeks, followed by cognitive-behavioral tests administered while CS was ongoing. Hippocampi of 12 mice were analyzed on a microarray chip. Old mice were more susceptible to the deleterious effects of CS reflected by significant (p<0.05) age by exposure interaction on two-way ANOVA: Old mice displayed a greater degree of weight loss and decreased cognitive functioning on the radial arm water maze and novel object recognition tests. In young females CS was not associated with weight loss but with modest improvement on RAWM and NOR test and decreased anxiety on the EPM. Using DESeq2, 580 miRNAs were analyzed. A higher expression profile was observed for miRNA-375 in the young CS group compared to the young control group (padj<0.05) and the old CS group (padj<0.05). The data suggest that CS has differential effects depending on age. Old mice were susceptible in terms of developing negative cognitive-behavioral effects whereas young mice displayed striking resilience. We hypothesize that selective expression of miRNA- 375 in young mice exposed to CS could help protect them against potentially deleterious effects of stress while positive effects that CS exposure has been shown to exert, could be supported. These findings have implications for a better understanding of the pathways of miRNAs triggered by CS in old and young individuals. Supported by: Israel Ministry of Science, Technology and Space, Japan-Israel Scientific Research Cooperation.
1Jerusalem Collge of Tecnology,Nursing Department; 2Eitanim Mental Nospital;
Postpartum depression ( PPD) is a disease which incorporates a variety of depressive signs differing in nature and severity .To assist in the understanding of the pathogenesis of the disorder, we aimed to ascertain a molecular mechanism underlying PPD development.We applied microarray technology to characterize gene expression of euthymic women with the history of PPD and compared the results with healthy controls .Our study demonstrated that women who considered euthymic on a clinical level, in fact, had altered molecular profile when compared with to participants with no PPD history. We identified nine genes with significantly distinguished expression in post-depressive women; they may serve as diagnostic tool for the detection of a predisposition to PPD .Our findings contribute significantly to the understanding of PPD etiology and its pathogenesis, offer a plausible explanation for the risk of the PPD recurrence, and may contribute to a treatment.
1Department of behavioral Sciences, The Psychobiological Research Center, Yezreel Valley College; 2Psychology Department, Tel-Hai College; 3Gordon College of Education, Haifa;
Emotional intelligence (EI) is associated theoretically and empirically with the ability to manage and regulate one’s own emotions. Most evidence in this venue, however, comes from self-report measures. This study tested the hypothesis that EI will be associated with more effective performance of an emotional task in which participants are asked to self-induce emotional arousal and then to relax. One hundred twenty-seven young adults performed the task while being monitored for their heart rate and blood pressure as indicators of emotional responsiveness and took tests of trait EI, ability EI, and trait anxiety. They also rated their subjective assessment of their own success in the emotional task. Structural equation modeling path analysis showed that ability EI, trait anxiety, and gender were associated with a factorial score of heart-rate differences, representing emotional regulation indicators. The associations suggested that people with higher ability-EI scores more effectively manipulated their emotional response when asked to. The results also showed negative correlations between ability EI and baseline blood pressure indicators (systolic and diastolic). The results are discussed in light of theory and existing evidence on the link between EI and emotional regulation.
1Dep. of Education and Psychology, The Open University; 2School of Behavioral Sciences, Tel Aviv-Yaffo Academic College;
Depression and anxiety are highly prevalent and considered of major public health concern worldwide. However, current pharmacological treatments for depression and anxiety are of limited efficacy and associated with various side effects, such as weight gain and sexual dysfunction. Thus, there is high demand for efficacious and safe treatments. In our previous studies, we have investigated the behavioral effect of the new herbal treatment (NHT) which consists of four Chinese herbs. It was found that both NHT and its primary herb induced anxiolytic- and antidepressant-like effects while precluding sexual dysfunction. The aim of the present study was to examine whether treatment with fractions isolated from NHT’s primary herb cause side-effects. To this end, mice were exposed to 4-week-long unpredictable chronic mild stress (UCMS), after which they were randomly assigned to 6 treatment groups: NHT (30mg/kg), escitalopram (15mg/kg), C-20 (3mg/kg), C-20 (30mg/kg), C-50 (3mg/kg) and vehicle. Following 3-weeks of treatment, anxiety- and depressive-like behaviors as well as sexual behavior and memory function were evaluated. Our results indicate that treatment with C-20 (3mg/kg) and C-50 (3mg/kg) induced beneficial anxiolytic- and antidepressant-like effects compared to vehicle, while the effects of C-50 were the most profound. In respect to side-effects, memory performance in the Morris water maze was not impaired by any of the treatments, including the fractions, compared to vehicle. Importantly, sexual function remained intact following treatment with the different fractions, as opposed to escitalopram. Taken together, these results show that C-50 (3mg/kg) herbal fraction is at least as efficacious as NHT and escitalopram in terms of anxiolytic- and antidepressant effects. In addition, treatment with the fraction did not cause memory deficits or sexual dysfunction. Thus, the benefit of the herbal fraction over escitalopram is in the preclusion of sexual dysfunction. Taken together, this c-50 herbal fraction may serve as a safer alternative to current conventional drugs for anxiety and depression. Key words: herbal treatment, Unpredictable Chronic Mild Stress, Selective Serotonin Reuptake Inhibitor, side effects.
1School of Behavioral Sciences, Tel Aviv-Yaffo Academic College; 2Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev;
Background: One of the problem areas of animal models of neuropsychiatric disorders is unclear reproducibility including external validity or generalizability. External validity can be evaluated by replications where aspects of the experiment are manipulated. Alternatively, it can be evaluated using systemic reviews and meta-analyses of available data, a standard practice in clinical research that is nearly ignored in animal models research. The present study reports a meta-analysis of the effects of antidepressant in the mouse forced swim test (FST), a standard screening models for antidepressant action. Methods: A comprehensive search of the literature identified papers that examined the effects of prototypic antidepressants from different groups in the standard protocol of the FST. Included were studies of imipramine, tranylcypromine, fluoxetine, bupropion and lithium. Effect sizes were estimated using Cohen’s d and effect size homogeneity was evaluated by the Q statistic. Results: (1) Despite the abundance of studies utilizing the FST in a variety of contexts, the number of studies that examine the effects of standard antidepressants, or used standard antidepressants as positive control was limited. (2) Across strains, for bupropion, tranylcypromine and lithium, as well as for the low dose range of fluoxetine and possibly the low dose range of imipramine, effects sizes across studies were not significantly different from each other (as shown by the q-statistics). (3) When there were enough experiments performed with a drug to allow separate examination of low and high doses, the effect sizes of the higher dose is qualitatively higher than the effect size of the lower dose. Discussion: these findings offer important support for the external validity of the FST, showing (1) an established antidepressant-like effect, (2) relatively stable effect sizes (3) dose response that is expressed across experiments and strains.
1Dept. of Molecular Biology, Ariel University, Ariel, Israel; 2Faculty of Medicine Bar-Ilan University, Zefat, Israel;
Background: Recent studies have demonstrated that commensal, probiotic, and pathogenic bacteria in the gastrointestinal tract can activate central nervous system (CNS) signaling systems, possibly through neural, endocrine and immune pathways, thus influencing brain function and behavior. This emerging concept of the microbiome–gut–brain axis suggests modulation of the gut microbiome as a potential novel therapeutic strategy for CNS disorders. In our laboratory, we selectively bred mice, from the WT sabra strain, with strong features of dominance (Dom) and submissiveness (Sub) that represent opposite poles of the behavioral spectrum. We hypothesized that Dom and Sub mice with opposing behavioral phenotypes may possess differential gut microbiomes and that modulation of the gut microbiome may alter depressive-like behavior. Results: Using 16S rRNA gene sequencing, we found Dom and Sub mice's gut microbiome to be comprised of significantly different ratios between bacterial phyla, attributed mainly to Bacteroidetes and Firmicutes. At the same time, the gut microbiome of WT mice, which represent a heterogeneous population displaying a mixed behavioral profile, was found to include Facteroidetes and Firmicutes bacteria, at a ratio approximately the average between that of Dom and Sub mice. WT sabra mice, transplanted with Sub and Dom-associated gut microbiota, exhibited changes in depressive-like behavior. Conclusions: Dom and Sub mice may be used for further investigation of the effects of the gut microbiome upon behavior. Targeted modulation of the microbiome may induce behavioral changes, leading to a better understanding of the role of the microbiome–gut–brain axis upon behavior.
1Molecular Psychiatry Laboratory - Department of Psychiatry, Hadassah-Hebrew University Medical center, Jerusalem, Israel; 2The Herman-Danna Division of Pediatric Psychiatry,Hadassah-Hebrew University Medical Center; Jerusalem Israel; 3Dept. of Mental Healthy. Israel Def. Forces., Jerusalem, Israel.;
Background: Early childhood adversity has been previously implicated with lifelong altered stress reactivity. Maladaptive stress reactivity may result in compromised neurocognitive and emotional regulation aptitudes and may lead to acute and chronic post traumatic stress disorder and depression. The current study explores the predictive value of blood based expression changes for identifying individual stress related vulnerability. Methods: Several hundred adolescent trainees undergoing combat military training were screened for exposure to early childhood trauma. An extremes case control sample compared those with high and low childhood trauma for prospective anxiety depressive and post traumatic symptoms, neuropsychological measures, and blood sampling, at rest and during exposure to extreme stress under simulated combat training conditions. Premorbid characteristics and neuropsychological and biological measures were employed to predict mal/adaptive outcomes following simulated combat. Results: Distinct blood expression profiles and psychological measures mark stress vulnerability and may help predict longer term outcomes before and immediately following exposure to trauma. Conclusion: Distinct signatures in blood may help focus preventive and interceptive efforts on vulnerable subjects during stress exposure and at its immediate aftermath, before chronic PTSD or depression develop. Results may further shed light on the role of inflammatory and neuro endocrine reactivity in mediating the transduction of stress into long term maladaptive neuropsychiatric outcomes.
1School of Behavioral Sciences, Tel Aviv-Yaffo Academic College; 2Department of Zoology, Tel-Aviv University; 3Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev;
The challenges to embody the complexity of mental symptoms and underlying biological mechanism of affective disorders questions the value of animal models as well as their reproducibility and validity. The validity is further hindered by the individual variability in many models. Whereas individual variability is a challenge, it can also be used to study susceptibility and resistance. One of the frequently used models for screening antidepressants and other interventions related to depression is the forced swim test (FST). The FST is usually performed only once however, several observations showed that repeating the FST, prolongs immobility time. Relating to the issues of both repeated testing, validity and individual variability, the current study was designed with a number of objectives: (1) Examine the group effects of repeated FST with and without chronic lithium (Li) treatment. (2) Examine the interaction between sex and repeated FST and (3) examine the consistency of individual variability across test and retest in the FST, with and without chronic Li treatment. As expected, repeated exposure to the FST resulted in increased immobility across exposures with no sex effect. Moreover, a significant correlation was established between the behavior in the second and third exposures suggesting an establishment of individual response to the test. As expected, chronic Li treatment resulted in a significant decrease in immobility time across exposures and sexes with a significant correlation between the performance of mice in the FST in exposure 1 and exposure 2 for both control and Li mice. These results suggest that at group level, immobility time increases across exposures although not always by the second exposure. Li is equally effective across exposures therefore it is possible that repeated testing protocols will have predictive validity. Additionally, mice show a consistent individual pattern of responding that is established either after 1 or 2 exposures.
1School of Behavioral Sciences, Tel Aviv-Yaffo Academic College; 2Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev;
Background: Lithium is the prototypic drug for the treatment of bipolar disorder. Despite its unique therapeutic profile, only a subset of patients shows a therapeutic response to treatment whereas others do not respond or show only partial response. This variability of response was suggested to be influenced by a complex network of genetic, epigenetic and environmental factors. One biological mechanism that had been repeatedly connected with lithium effects is stress. Significant research was done to study the effects of lithium of the outcome of different types of stress from cellular to organism levels. However, not only that lithium influences the outcomes of stress but it is also possible that stress influences the outcomes of lithium treatment. We previously demonstrated that animals that were chronically exposed to significant stress in the Unpredictable Chronic Mild Stress model or using chronic restrain showed a stronger response to the therapeutic-like effects of lithium in a number of tests related to bipolar disorder. The current study was designed to examine if such interaction is also apparent when milder stress is applied. Methods: ICR mice were used to examine (1) the effects of single versus group housing on the response to chronic lithium in the open field (OF) and the forced swim test (FST). (2) The effects of 3 weeks housing in constant dim light versus 12/12 hours light/dark cycle on the response to lithium in the OF, the FST and the elevated plus-maze (EPM). Results: (1) mice maintained in single housing show stronger lithium response in the FST compared with group housed mice. (2) The response to lithium in the FST was not influenced by constant dim light but affected the response to lithium in the EPM. Discussion: Combined with our previous results, the current data supports the possibility that lithium is more effective in stressed compared with non-stressed animals.
1School of Behavioral Sciences, Tel Aviv-Yaffo Academic College, Tel-Aviv; 2INSERM 930 & Department of Neurosciences Université François-Rabelais de Tours, France; 3Dept. of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beersheba ;
Background: The variability of individual responses to lithium treatment is a significant hurdle in the attempts to design the best treatment plans for bipolar patients. Unfortunately, only a subset of patients shows an excellent therapeutic response to lithium treatment whereas others do not respond or show only partial response. This variability of response was suggested to be influenced by a complex network of genetic, epigenetic and environmental factors. One biological mechanism that had been repeatedly connected with lithium effects is stress. To explore the possibility that stress can influence the effects of lithium, a previous study tested the interactions between mild stressors (single housing and light manipulations) and the effects of lithium whereas the current study was designed to test the interactions between more significant stressors and response to lithium in mice. Methods: ICR mice were used to examine (1) the effects of daily one hour restraint for three weeks on the response to chronic lithium in the open field (OF) and the forced swim test (FST). (2) The effects of exposure to the unpredictable chronic mild stress procedure on the response to lithium in a battery of behavioral tests including coat state, novelty suppressed feeding, grooming (splash) test, the forced swim test and the tail suspension test. Results: Whereas lithium and stress induced behavioral changes in many of the tests, a clear interaction between them was not frequent. However, in these infrequent events the effects of lithium appear to be stronger in stressed mice. Discussion: Combined with our results regarding mild stressors, the current data supports the possibility that lithium is more effective in stressed compared with non-stressed animals but that the interaction is limited to some but not all facets of behavior.
1The University of Haifa;
One of the greatest challenges surrounding human beings all over the world is successfully regulating emotions at time of distress. Although social agents may provide support in times of distress, studies to date have focused mostly on self-regulation. Emotional interpersonal synchrony has been researched and associated with varied positive social outcomes. Interpersonal synchrony is automatic and mediated through non-verbal communication including body and facial expressions. In the current study, we examine the impact of emotional interpersonal synchrony on one's emotions as a social strategy for emotion regulation. Given that synchrony communicates social support, we examined whether being in an emotional congruent state with a social agent diminishes distress. Following a manipulation of sad or happy mood induction, participants were presented with either happy or sad facial and body expressions. Our results indicate that being in a congruent emotional state, irrespective of the emotion, improves the emotional state of participants (diminishes distress and improves happiness). These results may offer novel insights into the mechanisms that underlie the interpersonal emotion regulation.
1Professor Emeritus Hebrew University of Jerusalem Director Mind Clinic ;
Intravenous Ketamine in Treatment Resistant Depression It is well known that Major Depressive Disorder (MDD) is common and it may affect up to 15-20% of the world population over their life-time. It has been shown that only approximately one-third of those acutely affected will respond to the first life of antidepressant treatment. The resistance to treatment (treatment resistant depression-TRD) may be as high as 40% of MDD patients. Many strategies to deal with TRD have been proposed including switching medications, augmentations regimes, transcranial magnetic stimulation, electroconvulsive therapy, and more recently treatment with ketamine. In this talk I shall cover various aspects of the treatment with ketamine: 1. The initial studies that led to the current state of use 2. The routes of administration of racemic ketamine and s-ketamine 3. The side effect profile of these compounds 4. The Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders 5. A summary of the proposed mechanisms of action of ketamine
1Department of Psychology and the Gonda Brain Research Center, Bar-Ilan University;
Animal models have greatly contributed to investigating the etiology of diseases and their underlying neurobiological mechanisms. Thus the availability of animal models for suicidality would potentially be valuable. Naturalists have basically failed to identify suicidal behavior in nonhuman species in field situations. Two key factors in suicidal behavior that cannot be readily modeled in animals are will and intention. However, antecedents, risk factors and biological mechanisms are some of the relevant aspects of suicidal behavior that may be modeled. Researchers have identified potential neuromechanisms, biomarkers and genes involved in suicidal behavior. Valid animal models would allow us to explore the role of these candidate mechanisms in suicidal behavior. To validate an animal model of behavior, a correspondence between the candidate model and the human phenomenon must be observed. This similarity should include, in principle, face validity, predictive validity and construct validity. The different attempts at modelling suicidality in animals will be presented; those based on stress-induced, self-destructive behaviors and those proposing that defeat and entrapment can lead to severe "helplessness" that, in turn, increases both morbidity and mortality, in animals. A more recent approach focuses on several main risk factors for suicidal behavior that can be modeled and manipulated in animals, including aggression, impulsivity, irritability and helplessness behavior (Malkesman et al., 2009). This modelling approach may be useful also for exploring the mechanisms underlying the risks of antidepressant use in in children, adolescents and young adults.
1School of Behavioral Sciences, Tel Aviv-Yaffo Academic College; 2Dept. of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev;
An important concern regarding animal models of psychopathology is their unclear external validity. One way to establish external validity is to examine measures that represent separate components of the pathology with a battery of tests performed in the same cohort of animals. Additionally, the utilization of the same animals in a battery of tests can help to reduce the number of animals used in research. However, the use of a battery of tests carries the assumption that animals will demonstrate pathology-like, or treatment-like behavioral changes across all the domains of a disorder modeled in the battery. For example, that individual mice that demonstrate high depression-like behavior in the forced swim test will also demonstrate high depression-like behavior in the sweet solution preference test. To examine this underlying assumption we tested intact male and female ICR mice in a battery of tests related to affective and anxiety disorders including spontaneous activity in the open field, sweet solution preference, elevated plus-maze, marble burying, hyponeophagia, forced swim test and amphetamine-induced hyperactivity. Against expectations, results do not show correlations between the behavior of individual mice in one test and behavior in other tests. No differences were found between the sexes. These preliminary results may suggest that the utilization of test batteries could be of limited validity and the interpretation of results for such experiments needs to be very carefully evaluated.
1University of Haifa, Department of Psychology; 2Ariel University, Department of Behavioral Sciences;
Loneliness is a subjective unpleasant experience that occurs when social relations are deficient. It is extremely prevalent, with harmful effects on physical and mental health. Lonely people demonstrate social deficits that make it harder for them to engage in a meaningful relationship. We propose a reduced ability to enjoy synchronization with others may contribute to their difficulties, as studies show that synchronizing with others is enjoyable, leading to a sense of connection and engagement. We employed a novel computer game to measure real-time motor synchronization among interacting participants. Each participant controls the movement of a circle inside a common arena, while seeing the movements of the other player. The players are directed either to move freely or to coordinate their movement. 46 participants (23 dyads) performed the sync task and completed the UCLA loneliness scale. While there was no significant difference in the ability of lonely versus non-lonely participants to achieve directed synchrony, there was an inverse correlation between loneliness and enjoyment from directed synchrony, which did not exist in the free movement condition. Furthermore, when we examined only very lonely and very non-lonely participants (+1/-1 SD from the mean loneliness score) the interaction between loneliness and game condition was significant. These preliminary findings help shed light on the behavioral underpinnings of lonely people’s social behavior.
1The Academic College of Tel Aviv-Yaffo; 2;
Victims of physical injuries commonly report substantial enduring implications for personal, emotional and social functioning. A recent study demonstrated that injury victims also reported higher incidence of general health problems and reduced health-related quality of life. The goal of the present study was to examine physiological and psychological mediators between past injury and health. Saliva samples from victims of past injury and non-injured participants were assessed for cortisol and IgA levels. In addition, participants completed a self-report health inventory questionnaire assessing illness prevalence, the short-form Medical Outcomes Survey (MOS SF-36) questionnaire, the Perceived Stress Scale, and the Life Orientation Test-Revised. Injured participants reported higher frequency of illness, mainly allergy incidences, compared to non-injured controls. Salivary cortisol levels were increased and IgA levels were marginally augmented in injured participants, however changes in these biomarkers did not explain the increase in illness incidence in the injured. In addition, injured participants reported poorer perceived health status, including reduced general health, physical functioning, and health beliefs. Perceived mental distress levels were similar in injured and non-injured participants, however, correlations between mental distress and self-reported medical outcomes were stronger in injured participants compared to non-injured controls indicating that previously injured individuals are more affected by daily-life stressors, resulting in poorer quality of life. Dispositional optimism was lower in injured participants, and optimism buffered the negative effect of stress on health perception. Thus, it is suggested that in injured individuals optimism played a protective role against the negative consequences of daily life stressors, thus improving health-related quality of life.
1The Academic College of Tel Aviv-Yaffo;
Physical injury is a stressful event that often results in physiological stress response, as well as increased perception of stress. In a previous study, victims of physical injury reported higher incidence of general illness and reduced health-related quality of life. The current study sought to examine the role of physical functioning perception on the association between past injury and health. We hypothesized that (a) the relationship between physical injury and morbidity is mediated by physical functioning perception, stress and health-related quality of life. (b) In injured individuals, better assessment of one's ability to return to full functioning after injury is associated with improved cognitive and emotional representations of the injury, reduced stress perception, and improved health and health-related quality of life. Victims of past injury and healthy controls completed demographic questionnaire, self-report health inventory questionnaire, Perceived Stress Scale, the Injury Perception Questionnaire and the Work Ability Index. Results indicate that physical functioning perception affects perceived stress, health and morbidity regardless to injury existence. Additionally, among injured people, positive correlation was found between physical functioning and health perceptions and negative correlations were found between functioning perceptions, perceived stress, emotional and cognitive representations related to injury, and morbidity. In other words, injured individuals assessment about their ability to return to full functioning after injury, associates with reduction of cognitive and emotional representations related to injury, perceived stress, which increase health and quality of life associated with health. These findings emphasize the importance of functioning perception on the cognitive and emotional changes that occur after injury and sharpen the understanding of stress as a risk factor for infectious diseases after injury.
1The Academic College of Tel Aviv Yaffo, Tel Aviv, Israel; 2Psychology Department, Rabin Medical Center, Beilinson Hospital, PetachTikva, Israel;
Physical injuries are common occurrences that can have substantial implications for mental health and well-being. Stress and emotional disturbances are associated with increased prevalence of general health problems, as well as reduced health-related quality of life. The goal of the current was to examine the role of injury perception, in terms of consequences, control, emotional effect and other aspects, on the association between bodily injuries, general health, and well-being. Two-hundred and forty victims of past injury completed a self-report health inventory questionnaire assessing illness prevalence during the six-month period prior to the study. In addition, they completed the short-form Medical Outcomes Survey (MOS SF-36) questionnaire, the Perceived Stress Scale, and the Injury Perception Questionnaire (InjPQ). Focusing on the emotional subscale of the InjPQ, we tested the mediating role of perceived stress and the emotional representation component of the Injury Perception scale on the association between injury severity and perceived health-related quality of life (MOS Total Scale). We found that in addition to the significant direct effect of injury severity on health-related quality of life, three significant indirect paths might account for this association. Stress and emotional representation each serve as individual, stand-alone mediators in this association, thus creating two separate indirect paths. Additionally, stress and emotional representation combined together moderate the relationship between severity and health perception. We concluded that while injury severity affects health perception of injured individuals, some of this effect may be the result of the stress that they experience and specifically, by the emotional representation of their injury, leading to that stress. All analyses were repeated controlling for sex, as it correlated with MOS. These analyses yielded essentially equivalent results.
1The Hebrew University Jerusalem, Israel;
Electroconvulsive therapy (ECT) is one of the most effective treatments for major depression. Although it has been used for decades, particularly for treatment of patients with antidepressant drug resistance, the mechanisms underlying ECT's action are still elusive. Our recent study on “depressed-like” mice reveals that the therapeutic effects of ECT are dependent on the presence of intact microglia and the levels of microglial activity. To elucidate the mechanism underlying the involvement of microglia in ECT’s effects we investigated the role of microglia in the effects of ECT on hippocampal adult neurogenesis. In general, neurogenesis, is considered an important mechanism for anti-depressive procedures. Here we specifically assessed the effects of ECT on the physical interactions between microglia and hippocampal adult neurogenic cells (doublecortin (DCX)-positive cells). ECT (3 sessions/week for 2.5 weeks) was administered to “depressed-like” mice (which were exposed to 5 weeks of chronic unpredictable stress (CUS), and was found to reverse the CUS-induced reductions in sucrose preference (anhedonia) and social exploration. These effects were microglia-dependent, evidenced by blockade of these therapeutic effects by the microglial inhibiting drug minocycline, or by near-complete depletion of brain microglia. We show that ECT induced increases in mRNA levels of the adult neurogenesis-related gene Sox11, and of DCX-positive neurogenic hippocampal cells. These effects did not occur when microglial activation was inhibited by minocycline. Furthermore, ECT induced a significant increase in the rate of physical interaction between microglia and DCX-positive cells, as assessed by confocal microscopy. In conclusion, we show that the anti-depressive effects of ECT are dependent on the presence and activity level of microglia in the hippocampus. Furthermore, the therapeutic effects of ECT seem to be mediated by the interaction of microglia with adult neurogenic cells.
1Department of Psychology, The Hebrew University of Jerusalem;
Despite impressive progress in our understanding of the molecular, cellular and circuit-level correlates of major depression, the biological mechanisms that causally underlie this disorder remain unclear, hindering the development of effective novel therapeutic procedures. Research in my laboratory demonstrates that microglial apoptosis, decline in numbers, and assumption of dystrophic morphology following chronic unpredictable stress (CUS), can trigger the development of a depressive-like condition in rodents. Consistently, microglia stimulating drugs, such macrophage colony stimulating factor, reverse the depressive-like condition in CUS-exposed rodents. Our studies further demonstrate that stimulation of microglial functions in "depressed-like" (CUS-exposed) mice underlies the anti-depressive effects of electroconvulsive treatment (ECT), as blockade of this stimulation (by CSF-1 antagonist or minocycline) abrogates the beneficial therapeutic effects of ECT on hedonic behavior and despair. The microglia-mediated effects on depression and its resolution involve modulation of adult neurogenesis, considered an important factor in the development of depression. Indeed, we found that microglia influence several aspects of the neurogenesis process, including the formation, elimination and maintenance of synapses on adult-born neurons, as well as the integration of these neurons into the brain circuitry. The interactions between microglia and adult-born neurons are impaired in depressed-like mice, and ECT increases neurogenesis by normalizing these interactions. Together, our findings provide a novel conceptualization of the cellular basis of stress-induced depression and offer microglia-related targets for the development of novel anti-depressive procedures.
1Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel; 2Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel; 3Department of Molecular Biology, Ariel University, Ariel, Israel;
MicroRNAs (miRNAs) are short single-strand RNA molecules that are not encoded into protein. These molecules regulate the post-transcriptional mRNA levels by base pairing. MiRNAs have recently been found to play a role in the pathophysiology of psychiatric diseases in general and depression in particular. Using Nanostring nCounter, we examined the expression of miRNAs in an animal model of depression- Flinder Sensitive Line (FSL) rats. Twelve miRNAs showed significant alteration in their expression levels, in Ventral Tegmental Area (VTA) compared to Sprague Dawley (SD) rats. These miRNAs were parallel altered in the serum of both male and female FSL in correlation with their motivation performance (immobility levels in forced swim test). Furthermore, some of these miRNAs' alterations were detected in the serum of depressed patients. These findings suggest the involvement of miRNAs in the pathogenesis of depression. We now test whether these miRNAs can serve as biomarker responding for anti-depressive treatment. Decoding the dynamics of miRNAs will ultimately help to identify molecular factors that may lead to recovery from depression.
1Hebrew University, Jerusalem, Israel; 2Posit Science, San Francisco, CA, USA;
Objectives: Mood disorders, such as major depressive disorder (MDD), are costly, recurring chronic medical conditions, with a lifetime prevalence of about 20%. Inhibitory control, the executive function process which enables individuals to maintain goal-directed behavior while ignoring irrelevant information, has been suggested as a potential causal factor in depression, and may therefore be an important therapeutic target in depression. However, results to date have been mixed. The goal of the current study was to test whether a novel, neuroplasticity-based inhibitory control training approach, delivered on mobile devices, is effective in alleviating depression. Methods: Adults with MDD were randomly assigned to either 2 weeks of inhibitory control training (ICT) or active control training (ACT) and were assessed for depression, anxiety and quality of life at baseline, after training and following 6 weeks of no-contact (follow up). Training was delivered through a mobile app (‘Moodify’), which also monitored momentary changes in mood. ICT included a go-no-go task which adaptively varied in difficulty based on individual progress. Results: ICT, but not ACT, group participants showed significant improvements in depression and anxiety scores following training. Similarly, quality of life significantly (mental subscale of the SF-12) improved for the ICT, but not the ACT, group. Improvements in depression remained for the ICT group participants at the 6-week follow up. In addition, baseline inhibitory control scores predicted improvements in depression following training, and were correlated with variability in mood ratings in the 2-week training period. Conclusion: Our findings show that a short, mobile inhibitory control intervention may improve depressive symptoms in MDD. The correlation between daily mood variability and inhibitory control further implies that such mood changes may significantly contribute to the link between inhibitory control and depression.
1Department of Clinical Biochemistry and Pharmacology; 2Psychiatry Research Unit; 3Faculty of Health Sciences, Ben-Gurion University of the Negev ; 4Mental Health Center, Beer-Sheva, Israel ;
Bipolar disorder (BPD) is a mental disorder with high heritability characterized by mood swings between depression and mania affecting the ability to function, resulting in cognitive and functional impairments and disruption in the life of the patients and their families. The etiology/pathophysiology of BPD illnesses is still unknown. Mitochondria are the main source of reactive oxygen species (ROS) in the cell. Rotenone, a mitochondrial complex I inhibitor, has widely been employed to induce an in vivo and in vitro Parkinson`s disease model causing extreme alteration in mitochondrial homeostasis, blocking autophagic flux by promoting increase in ROS (O2•− in particular) and by impairing lysosomal integrity. A parallel mitochondrial toxin is 3-nitropropionic acid (3NP), a complex II inhibitor. We are employing various concentrations of these two toxins on human neuronal cells (SH-SY5Y) to model very mild mitochondrial dysfunction assumed to occur in BPD. The mitochondrial parameters (mass, membrane potential and ROS) are monitored. Results: Cells were incubated with different concentrations of rotenone/3NP (10-105 pM; 1-103 nM, respectively) for 6, or 24 or 48 hrs. Cell viability was significantly decreased in a gradual manner both by rotenone and 3NP. There was a gradual increase in mitochondrial mass as a function of rotenone concentration only following 48 hrs. Mitochondrial membrane potential gradually decreased as a function of rotenone concentration. ROS levels were not affected. Conclusions: The decrease in cell viability and in mitochondrial membrane potential suggest that rotenone and 3NP treatment of SH-SY5Y cells may serve as a cell model for the mild mitochondrial dysfunction reported in BPD. The gradual increase in mitochondrial mass induced by rotenone might reflect a compensatory effort of the cells.
1Molecular Psychiatry Lab. Department of Psychiatry, Hadassah University, Hospital, Jerusalem, Israel; 2The Herman Danna Div. of Pediatric Psychiatry, Hadassah Hebrew University Medical Center, Jerusalem, Israel; 3Department of Obstetrics and Gynecology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel; 4Israel School of Computer Sciences and Engineering, Hebrew University, Jerusalem Israel;
Background: Altered immune cell reactivity during the development of depression after delivery, may point to biomarkers and potentially implicate underlying immune mechanisms. Methods: Genome scale mononuclear expression patterns after delivery were compared between mothers prospectively diagnosed with depression and resilient mothers. Results: Differential immune cell gene expression patterns associate significantly enriched pathways revealing altered immune function that accompany the triggering of postpartum depression. Pathway involvement implicate relevant immune candidates. Discussion: Differential mononuclear cell transcripts sampled postpartum point to unique immune activation among depressed mothers. Beyond serving as potential biomarkers, findings may point to pathogenetically relevant molecular targets involved in the development of depression.
1Tel Aviv Center for Brain Function, Tel Aviv Sourasky Medical Center, Tel Aviv University; 2Beer Yaakov Mental Health Center; 3Sagol School of Neuroscience, Tel Aviv University; 4School of Psychological Sciences, Tel Aviv University ; 5Faculty of Medicine, Tel Aviv University ; 6ELMindA;
Objective: This pilot research aimed to identify potential bio-markers that reliably predict the otherwise variable outcomes to deep repetitive Transcranial Magnetic Stimulation (rTMS) treatment in Major Depressive Disorder (MDD) patients. Methods: Thirteen MDD patients underwent functional Magnetic Resonance Imaging (fMRI) while performing two different tasks: 1. Gambling task 2. Implicit emotional regulation task. We used Region of Interest analysis within two limbic regions (“limbic A” and “limbic B”) known to display an impaired function in MDD patients during motivational and emotional regulation tasks, and explored whether these could predict treatment effectiveness. Following the fMRI scan, MDD patients were treated with four weeks of daily rTMS sessions. Results: Examination of the percent signal change (PSC) within the two limbic regions raised a significant reverse correlation in each task. In the gambling task a correlation was found between the “limbic A” PSC and the measured change in the Quick Inventory of Depressive Symptomatology (QIDS) questionnaire; In the emotional regulation task, a correlation was found between “limbic B” PSC and the change measured in the QIDS. Eventually, we combined these two predictors into one linear regression model and found each of them has a unique and significant predictability of treatment efficacy. Discussion: This study is the first to use multi-node limbic activity to predict response to rTMS treatment for MDD. These preliminary results suggest that these limbic emotional responses can be used as bio-markers for treatment success and thus should be considered when selecting rTMS treatment for MDD patients. Moreover, these results may suggest that rTMS treatment affects limbic reactivity in MDD, a hypothesis that should be further explored. However, these results should be interpreted carefully considering the small sample size and the lack of correlation with the more commonly used clinical outcome measure; the HDRS.
1Department of Psychology, University of Haifa, Haifa 3498838, Israel; 2Department of Biochemistry and Molecular Biology, New York Medical College Valhalla, New York 10595;
Exposure to an excessive or an uncontrolled stress is a major factor associated with various diseases, including post-traumatic stress disorder (PTSD). Although a number of available drugs have been used in clinical settings to explore the possible therapeutic avenues for treating PTSD, they still fall short due to limited response, high remission rates, and tolerability issues. However, there is a growing body of data pointing to a therapeutic potential in targeting the endocannabinoid (eCB) system and the neuropeptide Y (NPY) system for the prevention and treatment of PTSD. In this study, we aim to investigate the functional interaction between the eCB and NPY brain systems, in the effects of exposure to shock and reminders on post-trauma, anxiety and depression-like symptoms. In this PTSD model of exposure to shock and reminders, rats are exposed to a single footshock in an inhibitory avoidance apparatus followed by contextual situational reminders of the shock. We found that enahncing intra-BLA eCB or NPY1 signaling by injection of the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.1 µg) or the NPY1 receptor agonist Leu (10 pmol) after the shock, prevented the shock and reminders-induced increase in anxiety and depression like behaviors. The therapuetic effects of intra-BLA URB597 were blocked by co-adminstration of an NPY1 antagonist, suggesting that the effects of URB597 in the BLA are NPY1-dependnet. These results are the first step toward understanding the mechanisms through which NPY and eCB modulate stress-induced behavioral adaptation.
1Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel; 2Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel; 3Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada; 4;
NPY is an abundant neuropeptide in the brain. NPY receptors (NPY-R) role in stress processing has been extensively studied, and several reports indicate its crucial role in terminating stress response by counteracting the effect of CRH in the HPA axis. Using a state of the art whole genome epigenetic sequencing in combination with a PTSD-like rat model, we have found alteration in NPY-R programing (via DNA methylation) in the nucleus accumbens (NAc) of resilient rats, which is an important mood intersection for mediating reward. Moreover, 136 methylation sites showed a similar change, in both resilient and PTSD-like rats, from control rats (not exposed to trauma). These results led us to suggest these sites might represent the effect of the trauma, while the other subgroup-specific altered methylation sites (338 sites in PTSD-like rats, 445 sites in resilient rats) might relate to a cluster of genes that deviate resilience from susceptible phenotype. Interestingly, our results show that NPY receptor was the most significantly altered site, showing hypermethylation and lower expression in resilient rats, in comparison with control and PTSD-like rats. These results indicate that these receptors might be involved in the control mechanism of PTSD-like symptoms, which is opposed to the leading opinion on the role of NPY in PTSD. Further investigation of the role of this receptor would lead to a better understanding of the biological mechanism behind PTSD and resilience to it and might provide a new therapeutic target.
1Department of Psychiatry , Sheba Medical Center, Israel; 2Depatment of mental health, Ministry of health, Israel; 3Department of psychiatry, Sackler school of medicine, Tel aviv university, Israel;
Introduction: Employment is an important positive prognostic factor in psychiatry. Previous studies have shown that people with mental illness have a reduced capacity to work and are less likely to be employed full time. Unemployment reaches up to 95% in people suffering from severe mental illness. Objective: To demonstrate the occupational impairment in relation to a single and recurrent hospitalization due to a depressive episode. Methods: A national database containing consecutive admissions to all psychiatric facilities, including inpatient and day hospitals in Israel between 1990 and 2008, was linked to the database of the National Insurance Institute, which includes information on the income reported for the month of December during 1990–2010. In order to protect patients’ anonymity, data were encrypted before being transferred to the investigators for analysis. We examined the percentage of minimal wage gain in patients with a discharge diagnosis of depression, compared to that of the general population. Results: The proportion of patients diagnosed with depression who are earning above minimal wage was lower in comparison with the general population. Lower rates of income were found in people hospitalized due to recurrent depressive episode when compared to those hospitalized due to a single episode. Findings were similar in all age groups and in both men and women. Conclusions: Our findings support the hypothesis that people hospitalized due to depression are less likely to reach gainful employment and to return to productive life, especially after multiple admissions.
1University of Haifa, Department of Psychology;
Loneliness is a subjective unpleasant experience that occurs when social relations are deficient. It is an extremely prevalent human phenomenon, with harmful effects on physical and mental health. Lonely people demonstrate a host of social deficits that make it harder for them to engage in a meaningful relationship. A potential important component of the failure to be fully engaged in social interactions may be related to difficulties in reaching alignment or synchronization with others. Studies show that not being able to synchronize effectively can result in lowered sense of affinity and connection, lower engagement and lower satisfaction from the interaction. These all relate directly to the experience of lonely people. However, to the best of our knowledge, no study to date has examined directly the ability of lonely people to be synchronized. In the present study, we employ a novel paradigm to measure real-time motor synchronization among interacting participants using a computer game. Each participant uses four arrows to move a circle inside a common square arena, while seeing the movements of the other player. To examine the relationship between synchrony and loneliness we recently carried out a preliminary study with 40 participants (20 dyads) who performed the sync task and completed the UCLA loneliness scale. As hypothesized, the mean loneliness score of the dyads (the average loneliness score of both players) was significantly negatively correlated with their ability to synchronize. Moreover, in the group of dyads with a high loneliness score movement correlation between participants was significantly lower in comparison to the group of dyads with a low loneliness score. These preliminary findings help shed light on the behavioral underpinnings of lonely people’s social behavior. They pave the way to additional behavioral as well as neural investigations, as the sync game setup allows it to be used during neuroimaging as well as neuro-stimulation studies.
1University of Haifa; 2;
Aim: Attachment theory is one of the most investigated theories for understanding interpersonal relationships. Research suggests an association between patient' attachment orientations, therapeutic alliance and treatment outcome. A great deal of the existing literature on attachment focuses on patients’ self-report and structured interviews, therefore conveying what patients are able and willing to report thus suffering from shared variance. Attachment theory and research posit that individuals do not always provide accurate information, and individuals high on insecure attachment orientations may provide distort reports, especially on their relationships and mental health. The present study aims at overcoming these difficulties by using both explicit and implicit measures of patients’ expectations from the therapist. Method: Twenty-five patients with a diagnosis of major depressive disorder (MDD) receiving supportive-expressive short term dynamic psychotherapy participated in the current study. Attachment orientations and expectations from the therapist will be examined before treatment and four times during treatment using both explicit, patients’ self-report measures and implicit, lexical decision task, measures. Results: Analysis is now being conducted and will be presented at the ISBP meeting in March 2018. Discussion: This study will shed light on the patient’s explicit and implicit expectations from the therapist and association to outcome.
1The Academic College of Tel Aviv Yaffo;
Serious nonfatal injuries are common occurrences that can have substantial implications for personal and social functioning. Serious injuries are frequently associated with lasting mental health issues such as depression, panic disorder, generalized anxiety disorder, and substance abuse. The goal of the present study was to examine long-lasting implications of injury to general health and wellbeing. In addition, the moderating role of stress perception on the association between injury and general health were assessed. Two-hundred and forty (48.9%) injured (0.5-10 years post injury) and 251 non-injured subjects completed a self-report health inventory questionnaire regarding their health status during the 6 months prior to study, the short-form Medical Outcome Study (MOS) questionnaire and the Perceived Stress Scale (PSS). Results show that injured subjects reported worse medical outcomes in 3 out of 5 MOS subscales: General health, physical functioning and health beliefs, as well as in the total scale. In addition, injured men reported higher incidence of upper respiratory infections and fever compared to non-injured men, while in women, injury was not associated with increased incidence of illness. Moreover, correlations between perceived stress and self-reported medical outcomes were higher in injured subjects compared to non-injured, suggesting that injury moderates the association between stress and wellbeing. The results of the current study indicate that physical injuries are associated with long-lasting implications for health and wellbeing. In men, severe injury is also associated with increased incidence of illness, suggesting a role for gender in mediating the effects of physical injury. This study highlights several factors that contribute to health and wellbeing following physical injury and may assist in providing better multi-disciplinary care for the injured.
1Interdisciplinary Center Herzliya; 2Interdisciplinary Center Herzliya; 3Beer Yaakov Medical Center;
Data suggest that 19-45% of all births are described by mothers as traumatic, eliciting subjective experiences of threat for physical integrity of the self and/or newborn. Approximately 25% of women develop symptoms of post-traumatic-stress-following-childbirth (PTS-FC), and 4-15% culminate into full post-traumatic-stress-disorder (in normative and high-risk populations respectively). Furthermore, PTS-FC may increase risk for difficulties in the emerging mother-infant relationship, and associated infant-outcomes. While prevalence and risk factors of PTS-FC are well documented, several domains warrant further empirical attention: Prospective studies which assess predictive models, are limited. These are necessary for developing optimal screening of vulnerabilities both prior to childbirth and particularly during the postnatal hospital-stay. Such models are key in informing preventive policy pertaining to perinatal-care. The current presentation utilizes data from a longitudinal cohort to chart the development of symptoms of PTS-FC. We use longitudinal data-driven classification techniques to delineate trajectories of PTS-FC and we identify a particular class of women whom are at high-risk for presentation of persistent stable symptoms during the first four months postpartum. Next, using behavioral observations of mother-infant interactions, we examine the risk and detrimental impact that these symptoms pose on the developing mother-infant relationship. Finally, we empirically assess our ability to effectively identify women at risk during the postnatal hospital stay. Results inform preventive policy pertaining to perinatal care.
1Department of Psychiatry, NYU Langone Medical Center;
Since its initial inclusion in DSM III (1980) Post-traumatic Stress Disorder (PTSD) received much professional and public attention. It also became a template for basic research and animal models. Throughout that period, however, PTSD has been the object of restless revisions, re-classification, and debates. Moreover, the disorder’s conditional prevalence today resembles that recorded before its inception. Its therapies are locally efficacious, but globally inefficient. There are raising doubts about its validity as an outcome of biological studies. Is it dying therefore? Deemed to become obsolete? Are some of PTSD’s afflictions shared by other mental disorders? Else, how can one understand the causes of PTSD’s increasing troubles, and what remedies might be offered such that future research advances knowledge rather than err? Trauma survivors, multiplying just a few miles from the conference venue, require that we correct course, and such is the thrust of this presentation.
1The Academic College of Tel Aviv-Yaffo;
Maternal depression during pregnancy is associated with unfavorable outcomes for the offspring. Pregnant women suffering from mood disturbances commonly use selective serotonin reuptake inhibitor (SSRI) antidepressants. The beneficial effects of SSRI on the core symptoms of depression are well documented. However, evidence suggest that SSRIs readily cross the placental barrier and impact the developing fetal brain. The goal of the present study was to examine the effects of prenatal stress, as a model for maternal depression, and prenatal exposure to fluoxetine, on the response to an immune challenge in mice. Pregnant dams were injected with either saline or fluoxetine throughout pregnancy. Offspring were administered with lipopolysaccharide (LPS) and circulating levels of proinflammatory cytokines were assessed. Prenatal fluoxetine augmented interleukin (IL)-1beta response while suppressing TNF-alpha and IL-6 secretion in an age-and sex-dependent manner. Moreover, sickness behavior induced by LPS was blunted by prenatal fluoxetine. A separate study examined the effects of prenatal stress in combination with fluoxetine on the response to LPS. Prenatal stress significantly augmented the behavioral response to the immune challenge. Prenatal fluoxetine did not prevent these responses, and, in many cases, augmented them. Lastly, an additional study assessed the effect of prenatal fluoxetine on the response to stress. Prenatal fluoxetine augmented most aspects of corticosterone response to continuous or acute stress. The dexamethasone suppression test revealed that prenatal fluoxetine induced a state of glucocorticoid resistance indicating that the negative feedback control of the hypothalamic-pituitary-adrenal (HPA) axis was disrupted. These findings provide the first indication for altered response to an immune challenge following in utero SSRI treatment and suggest a role for the HPA axis in modulating the effects of prenatal SSRI. This study may contribute to the understanding of the effects of prenatal environment on the development of the neuroendocrine and immune systems and the interplay between these systems. Furthermore, these findings may assist in understanding the limitations and precautions that should be taken in the use of SSRIs during pregnancy.
1The Herman-Danna Division of Pediatric Psychiatry, Department of Psychiatry, Hadassah - Hebrew University Medical Center; 2Molecular Psychiatry Laboratory - Department of Psychiatry, Hadassah - Hebrew University Medical center;
Backgraound: Eating Disorders (ED) incidence increases in recent years for unkown reasons, with the most severe form of restrictive Anorexia Nervosa (AN) affecting up to 1% of adolescent girls, of which up to one half recover, another third recover only partially, and the rest suffer a chronic treatment refractory course. Major biological determinants mediating risk for ED remain obscure. Aims: To prospectively charcterise ED patients based on main clinical course charecteristics, prognostic factors, associated mental and physical complications, and treatment response, and locate biological and psychological markers and predictors and causaly involved contributors, for expressing ED and for its psychiatric and medical course and prognosis. Methods: ED patients reffered to the ambulatory clinic, day care facility and in patient unit of the Herman Dana Child Psychiatry Center are approached to volunteer to the study. Data collected include comprehensive psychological assesment, plasma levels of candidate hormones, neurotransmitters and proteins, immune cell protein and RNA levels, in search of correlations with symptoms and prognostic indices. Results: We will report results of the preliminary analyses of the prospective cohort thus far collected from this ongoing study.
1Department of Psychology, University of Haifa, Israel.; 2Sagol Department of Neurobiology, University of Haifa, Israel.;
Chronic pain is a highly prevalent and disabling condition, which is often co-occur with depressive and anxiety disorders. Interestingly, several animal studies have demonstrated a reduction in neurogenesis in the hippocampal Dentate Gyrus (DG) in both: chronic pain and anxio-depressive animal models. However, as most chronic pain studies did not differentiate between the individuals based on their emotional status, it remained unclear whether the reduced rate of hippocampal neurogenesis is related to the pain itself, or rather to the emotional complications that often co-occur with it. In order to address this question, we used a rat model of chronic neuropathic pain, and assessed anxio-depressive behavioral changes using a battery of behavioral tests. Later, we applied the behavioral profiling approach that allowed us to differentiate and compare between emotionally affected and resilient individuals within the pain group. The results demonstrate that only the emotionally affected animals differ significantly from the sham-operated group with regard to the neurogenesis rate in the dorsal DG. Thereby, we showed that the effect of chronic pain on the hippocampal neurogenesis is associated with emotional comorbidity. In light of our results, the presence of emotional comorbidity may require different treatment strategies for managing chronic pain conditions.
1Faculty of Life Sciences; 2Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel ;
Major depressive disorder is a severe psychiatry disease which affects approximately 5% of the population in any given year. Despite the notable progress that has been made in understanding the mechanism of depression, the efficacy of current treatments remains inadequate, and a considerable percentage of patients exhibit low response rate to the antidepressant treatments. Electrical Deep Brain Stimulation (DBS) of the subgenual-cingulate-cortex was previously shown to have a significant long lasting effect of alleviating the symptoms ofdepression. This region in human parallels the medial prefrontal cortex in rats and is known to have a direct connection to the VTA .Recent studies suggested that stimulation of the ventral tegmental area (VTA), decreased depressive-like symptoms in a genetic rat model of depression (Flinders Sensitive Line rats). The pattern of the stimulation was designed to simulate the burst firing of a healthy rat, suggesting that the abnormalities are caused by dysfunctional network system. Herein, we aimed to study the effect of laterally stimulating the ventro-medial Pre-Frontal Cortex (vmPFC) on the VTA electrophysiology functionalityin FSL rats. We found that chronic (5 days) bilateral low frequency stimulation of the vmPFC (15min per day) caused a significant long-term improvement of depressive-like behavior in the Forced Swim Test ,the saccharin consumption test and normalized the VTA local field potential activity (LFP) in comparison to unilateral stimulation and sham rats as a control group. We suggest that bilateral deep brain stimulation is more effective than unilateral stimulation, depends on the pattern of stimulation, in the vmPFC in improving depressive-like symptoms in a rat model of depression.
1Department of Psychiatry, Tel Aviv Sourasky Medical Center ; 2Functional Brain Center, Wohl Institute for Advanced Imaging, Tel-Aviv Sourasky Medical Center; 3Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel; 4Teeside University, UK;
Introduction: Premenstrual dysphoric disorder (PMDD), a chronic, recurrent and disabling mental disorder affects 3–8% of women of reproductive age worldwide. Available treatment possibilities are limited. Neurofeedback (NF) training is presumed to help in the self-regulation of brain networks. The current study explored the benefits of this novel therapeutic approach for PMDD patients. Method: 24 women diagnosed with PMDD according to DSM-5 criteria, underwent 3 months of EEG-NF training in a double-blind randomized study design. The protocol consisted of two study groups differing in the neural probe in which the feedback given to the subjects was derived from. 16 patients were randomly assigned to a group that received feedback based on an amygdala electrical fingerprint (amyEFP) probe. The second group of 8 patients received feedback based on frontal alpha asymmetry calculations. Clinical outcomes were assessed by daily self-rating questionnaires as well as monthly psychiatric evaluations and observer-filled questionnaires (The Premenstrual Tension Syndrome, PMTS-O). The lasting effect of NF was evaluated 3 months after training ended. Results: After competion of NF training, patients from both groups showed significant reduction in PMDD core symptoms according to the PMTS-O, but only patients from the EFP group retained this improvement three months after the training ended. This group of patients showed reduction in the sum of all symptoms (p<0.0001) and in the sum of the 4 core symptoms of PMDD, emotional lability, anger, anxiety and depression (p<0.0001). Discussion: EEG-NF training, via an amyEFP probe targeted to enhance emotional regulation, resulted in lasting improvement of PMDD symptoms. These results suggest a therapeutic role for this non-pharmaceutical treatment method for PMDD, and warrant further studies to assess the effectiveness of this tool in a wide range of clinical populations suffering from mental disorders effecting emotional regulation
1Eve clinic, Sheba Medical Center, Tel Aviv ;
Parturition is a time of multi-aspect changes: biological, personal, social and more. Hormonal changes play a major role in parturition and in the postpartum period. This is a time of radical change in sex hormone levels as well as changes in the HPA system; specifically in cortisol. Women who are sensitive to hormonal changes are at a high risk of developing mental changes, such as depression and psychosis. Although postpartum depression is highly prevalent, affecting approximately 15% of new mothers, few therapeutic options have been thoroughly explored. Long-term treatment of women undergoing mental changes in the postpartum period is controversial. Treatment options are hormonal, psychotropic medication, hospitalization, psychotherapies and more, and must meet the needs and wishes of women and their family, as well as protect the mother and her child and the dyadic relationship. The literature shows that women who need pharmacotherapy with an antidepressant are at risk of developing bipolar affective disorder. Women requiring more than one medication have a tenfold increased risk of developing bipolar affective disorder. Women needing postpartum hospitalization have a 46.4 times higher rate of a recurrent postpartum episode, after a subsequent birth, compared to women with no postpartum affective disorder. I will present a case study of a woman who was hospitalized with postpartum depression after her first delivery, together with her newborn baby. This woman was treated intensively with medication during her second pregnancy and postpartum, and closely monitored, without medication, throughout her third pregnancy and postpartum. Further research is urgently needed to correctly identify postpartum depression etiology, and short and long term treatment, in order to improve outcome.
1Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer; 2Sackler Faculty of Medicine, Tel Aviv University;
Introduction: Major depressive disorder (MDD) is a common comorbidity of eating disorders (ED), associated with worse ED outcome and higher rates of suicidality. Patients with ED have a very poor response to antidepressant medications. Although electroconvulsive treatment (ECT) is highly effective in the treatment of refractory cases of MDD, to our knowledge there are only a few anecdotal reports on ECT in ED and only 3 cases treated with ECT have been reported for adolescents with ED. Objective: We present a comprehensive case series of 35 ED female adolescents who received ECT for treatment resistant depression, and reports the side effects and effectiveness of ECT on depression, suicidality and severity of ED symptoms. Methods: A retrospective analysis of all adolescent inpatients, age 12 to 19 years (N=35), treated with ECT during the period 1998- 2017, at the Inpatient Department for Adolescents with Eating Disorders at Sheba Medical Center. Inclusion criteria included a diagnosis of ED and comorbid severe MDD refractory to at least two antidepressants, or the occurrence of active suicidality. The global severity of eating disorder symptoms, depression and suicidality, were assessed by the Clinical Global Impression (CGI) Scale Severity (CGI-S) and Improvement (CGI-I). Reports from file on side effects were also collected. Results: 31 patients (89%) completed the recommended ECT procedure with mean of 15 ECT sessions. Clinical improvement at the end of the ECT treatment based on the CGI-I I (1- very much improved or 2- much improved) were the following: 42% for ED, 85% for depression and 80% for suicidality. The majority of patients did not report any adverse effects. Four patients (11.5%) experienced transient memory impairment. Conclusions: We describe the largest group to date of adolescents diagnosed with ED and comorbid MDD treated with ECT. Based on our experience ECT is safe, well-tolerated and potentially effective treatment for adolescents with ED comorbid with MDD and/or suicidality.
1Psychiatric Department, Tel Aviv Medical Center, Israel ; 2Lis Hospital, Tel Aviv Medical Center, Israel; 3Faculty of Medicine, Tel Aviv University, Israel;
Introduction: Fertility treatments often result in extreme emotional distress to women undergoing the procedure. This distress is obviously partly due to the psychological and physiological strain involved in the process. We have previously shown that the extreme hormonal fluctuations that underlie the procedures also contribute to the emotional destabilization, especially in women with a history of mental disorders. It is not known whether women with a psychiatric condition respond differently to hormonal intervention cycles versus natural cycles during intrauterine insemination procedures. Method: 240 women undergoing three different intrauterine insemination protocols – gonadotropin induction, Ikaclomin (clomifen) induction and natural course - were assessed for underlying psychiatric conditions and psychological traits before entering a treatment cycle. All women who completed both a full SCID interview and the psychometric evaluations were followed up over one or more treatment cycles and assessed before insemination (high estrogen time point) and 2 weeks afterwards before βHCG results (high progesterone when pregnant). Results: Ninety six women completed a full follow up over at least one cycle and 89 completed both the SCID interview and the psychometrics. Estrogen levels in both hormonal protocols were more than 2 times higher than during a natural cycle. Our preliminary data show that women with any past psychiatric condition (42%) are more symptomatic during fertility treatments. Furthermore, these women, whether presenting with a psychiatric diagnosis, or when characterized by their level of Neuroticism, respond significantly more dramatically to the hormonal cycles than to natural ones during the high estrogen phase. Discussion: In this preliminary report, we were able to show the increased mood sensitivity of women with depressive and anxiety diagnoses and women with high neuroticism to the insidious estrogenic surge during infertility treatments. We also show that cycles that are precipitated by hormonal treatment reach levels of estrogen that are twice higher than those achieved in natural cycles, and that these cycles are more symptomatic in neurotic women. Women with a psychiatric mood or anxiety condition or who are highly neurotic and are undergoing hormonal intrauterine insemination protocols may be predisposed to deterioration in their mental state.
Background Lithium is the prototype of mood-stabilizing drugs. The inositol-depletion hypothesis proposes that lithium attenuates phosphatidylinositol signaling. Knockout mice of two genes negatively-regulated by lithium (IMPA1 or Slc5a3), each encoding for an inositol metabolism-related protein were previously characterized as exhibiting a lithium-like neurochemical and behavioral phenotype. Results We performed a microarray study searching for pathways affected by chronic lithium treatment and by the knockout of each of these genes. Bioinformatics analysis indicated up-regulation of mitochondrial-function in the frontal-cortex of all three groups. As a potential behavioral correlate of the bioinformatics results we examined the effect of rotenone, a mitochondrial-function inhibitor, in the forced-swim test and the amphetamine-induced hyperlocomotion paradigm. The observed interrelationship between lithium and rotenone, namely, that the two drugs counteracted each other's effects in both behavioral tests, is consistent with the result of the bioinformatics analysis. Further, a proteomics analysis in the frontal-cortex of lithium-treated mice and IMPA1-knockout mice was carried out to test whether the upregulation of mitochondrial genes is reflected at the protein level. Twelve proteins were similarly affected by lithium-treatment and IMPA1-knockout, eight of them related to mitochondrial-function and/or autophagy. Since lithium's induction of autophagy in-vitro has been shown to be mediated by inositol-depletion we further assessed autophagy markers levels. Both lithium-treatment and IMPA1-knockout resulted in elevated beclin-1/p62 ratio indicative of increased autophagy, corroborating our proteomics results. Conclusions The results suggest the involvement of mitochondrial-function and autophagy in the mood-stabilizing effect of lithium in an inositol-metabolism mediated manner.
1Beer Yaakov Mental Health Center, Tel Aviv University; 2Bar Ilan University; 3Center for Brain Functions, Tel Aviv Sourasky Medical Center; 4National Institute of Mental Health NIMH;
Background: A typical phenomenon in depression is the tendency for ruminative thinking, a persistent thought pattern revolving around self-referntial negative affect. Another consistent finding in depression is aberrant ventral striatal (VS) activity when anticipating and receiving rewards. A tendency for negative self-referential thought may influence how external rewards are anticipated and processed. However, to date, no study examined the neural link between rumination and VS activity during reward-related processing. This study aimed at exploring this link using functional magnetic resonance imaging (fMRI) in healthy and depressed participants with different levels of trait rumination. Methods: We scanned a sample composed of 51 healthy participants and 17 participants diagnosed with major depressive disorder while performing a gambling task that includes an anticipatory phase prior to receiving an uncertain monetary reward or loss outcome. Participants also completed the Beck Depression Inventory (BDI) and the Ruminative Response Scale (RRS) assessing trait depression and rumination, respectively. Results: Across the sample, RRS scores correlated negatively with VS activity during outcome anticipation. This correlation remained significant even after controlling for BDI scores, suggesting its specificity to rumination. Furthermore, a hierarchical multiple regression analysis showed that RRS scores moderated the association between VS activity during outcome anticipation and, specifically, reward outcome processing, even after controlling for demographic variables and depression symptom severity. Discussion: Our results suggest a link between negative, self-referential thought tendencies and processing of external rewards. These findings may contribute to elucidating the association between depression, rumination, and aberrant reward-related processes.
1Wayne State University Department of Biological Sciences; 2Weizmann Institute of Science Belkin Visiting Professor;
Depletion of inositol has profound effects on cell function and has been implicated in the therapeutic effects of drugs used to treat bipolar disorder. We have previously shown that valproate (VPA) depletes inositol in yeast and human cells by inhibiting myo-inositol 3-phosphate synthase, the enzyme that catalyzes the first and rate-limiting step of inositol biosynthesis. More recently, we have determined that VPA and inositol depletion decreases V-ATPase activity and proton pumping in isolated vacuolar vesicles. Perturbation of the V-ATPase is a consequence of altered PI3,5P2 homeostasis under inositol-limiting conditions. Both PI3,5P2 and the V-ATPase are required for endocytic trafficking. We now demonstrate that VPA delays endocytosis in yeast and mammalian cells, and propose inhibition of endocytosis as a novel mechanism whereby VPA may elicit its GABAergic effect.
1אוניברסיטת תל אביב;
מטרה: לתאר מדגם של אשפוזים פסיכיאטרים בשנה הראשונה לאחר לידה באונטריו קנדה, על מנת לקדם את ההבנה של המאפיינים ותתי הקבוצות באוכלוסיית המאושפזות. שיטות: אספנו מידע על כל האשפוזים הפסיכיאטרים (1702), בשנה הראשונה אחרי לידה ב- 2007-2012 באונטריו קנדה באמצעות מאגרי המידע הקנדים. המידע כולל פרטים סוציו-דמוגרפים, היסטוריה פסיכיאטרית, סטטוס האשפוז, אבחנה ומהלך האשפוז. כמו כן נבדקו שלושה מדדים פוסט אשפוזיים בשבוע, בחודש ובשנה לאחר השחרור: מעקב בקהילה, ביקור בחדר מיון ואשפוז מחדש. נבדקו שלוש שאלות מחקר: 1. אשפוזים פסיכיאטרים ראשונים בשנה הראשונה לאחר לידה: השוואה לנשים עם היסטוריה של אשפוזים פסיכיאטרים 2. אשפוזים פסיכיאטרים קצרים בשנה הראשונה לאחר לידה (72שעות >): השוואה לאשפוזים ארוכים (72שעות <) 3. חקירת תת הקבוצות שמרכיבות את אוכלוסיית המאושפזות אשפוזים פסיכיאטרים קצרים בשנה הראשונה לאחר לידה (72שעות >) על ידי(LCA) latent class analysis תוצאות: באוכלוסיית המדגם 2.6 מתוך 1000 יולדות אשפוזו אשפוז פסיכיאטרי בשנה הראשונה לאחר לידה. רב האשפוזים היו אשפוזים ראשונים (59%) אך הסיכון לאשפוז פסיכיאטרי בשנה הראשונה לאחר לידה היה גבוה פי 28 אצל נשים עם אשפוזים בעבר. רק 15% מהאשפוזים היו בחודש הראשון לאחר הלידה. כמעט מחצית מהאשפוזים היו בכפיה (45.2%) ויותר ממחצית בשל איומים בפגיעה עצמית (55.9%). הסיבה העיקרית לאשפוז לא הייתה הפרעה פסיכוטית או ביפולארית אלא הפרעה אפקטיבית (47%). אשפוזים קצרים בני פחות מ- 72 שעות היוו 37% מהאשפוזים והיו בעיקר בנשים ללא אשפוזים פסיכיאטרים בעבר (83.3%), עם פי שלושה דרישה לשחרור בניגוד להמלצת הרופאים. באמצעות LCA הבחנו בארבע תתי קבוצות באוכלוסיית האשפוזים הקצרים: נשים ללא היסטוריה פסיכיאטרית, נשים עם היסטוריה של מחלה פסיכוטית, נשים עם היסטוריה של מחלות אפקטיביות וללא אשפוזים פסיכיאטרים ובנות עשרה עם שימוש בסמים ואלכוהול. מסקנות: באמצעות מאגרי המידע הרפואיים באונטריו קנדה, תארנו 1702 אשפוזים פסיכיאטרים לאחר לידה. הצלחנו לאפיין תת קבוצה של נשים ללא היסטוריה של אשפוזים פסיכיאטרים וקבוצה של נשים עם אשפוזים קצרים בני פחות מ- 72 שעות. הבנה של תתי האוכלוסיות המתאשפזות יכולה לסייע במניעה של אשפוזים אלו, הגברת ההיענות לאשפוז כאשר הוא בלתי נמנע ויצירת מסגרות אשפוז מותאמות.
Anxiety and obsessive-compulsive disorders
1Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel; 2Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel;
5HT2CRs are Serotonin receptors that are broadly expressed in the CNS and play roles in varied behavioral and physiological processes including emotion and reward. The 5HT2CR mRNA undergoes adenosine-to-inosine RNA editing at five positions (sites A–E) resulting in expression of differently edited isoforms in specific brain regions. 5HT2CR RNA editing has been shown to modulate receptor functions including 5-HT potency, agonist binding affinity, constitutive activity, and G-protein-coupling activity. In this study we examined the RNA editing of the 5HT2CR in a rat model for Post-traumatic-stress-disorder (PTSD), in the central amygdala. The central amygdala is a key structure mediating the effects of stress on the consolidation and recall of traumatic memories. We found significant differences in the frequency of the VNV cluster (partially edited isoform) and the INI cluster (unedited isoform) between the resilient and susceptible groups. Consequently, treating the susceptible rats with a 5HT2CR specific antagonist had long lasting effect on PTSD-like behavior improvement. These results provide potential mechanistic explanation for susceptibility to traumatic events that may develop PTSD. It is intriguing to think this study may suggest a new site to medical intervention.
1University of Haifa;
Fear overgeneralization is a central mechanism in anxiety disorders. To reduce symptoms related to overgeneralization, a novel perceptual discrimination-training task was developed. In a previous study we showed that improvement in basic perceptual learning enhanced discrimination between threat and safety cues (Ginat-Frolich et al., 2017). The current study assessed the effects of this training task among adults with high spider fear with the goal of reducing their avoidance behaviors towards spider-related stimuli. Participants were recruited based on fear of spider questionnaire, and were then randomized into training or placebo conditions. Following the assigned task, participants completed a behavioral-approach task (BAT) consisting of 5 spider –related stimuli, ranging from a paper spider to a live tarantula. Participants were asked to bring the stimulus as close to themselves as possible, while distance, time and self-reported measures were collected. Next, participants completed a threat-safety discrimination task using schematic morphs ranging from a flower to a spider, while eye-tracking and GSR measures were collected. Finally, participants were shown a task consisting of paired spider and neutral images, while eye-tracking data was recorded. Results of 51 participants showed the efficacy of the training task in the discrimination test as well as decreased avoidance behavior in the training condition.
1BBB-Group, The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel; 2Gonda Brain Research Center, Bar Ilan University, Ramat-Gan, Israel; 3Department. of Education and Psychology, The Open University; 4School of Behavioral Science, The Academic College, Tel Aviv Yaffo; 5The Interdisciplinary Center, Hertzlia, Israel; 6The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel; 7Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY, 10029, ;
The blood-brain barrier (BBB) is a barrier that hinders the entry of most molecules into the brain. Disruption in the BBB can lead to multiple brain pathologies. It was demonstrated that frequent BBB disruption in the human cerebral cortex was associated with molecular, clinical, and physiological stress-associated indices. It was also shown that chronic mild stress decreased the activity of superoxide dismutase, thereby increasing oxidants which in turn disrupt the tight junction proteins of the BBB. The aim of this study was to examine the effect of acute and chronic mild stress on the BBB. For that we used unpredictable chronic mild stress (UCMS) paradigm and detected BBB disruption using sodium fluorescein (NaF) injection. ICR mice were randomly assigned to the following four groups: 4-weeks UCMS (N=11), 2-weeks UCMS (N=11), acute stress (30 min; N=14) and non-stressed mice (N=10-14). After exposure to stress, mice were i.v. injected with NaF for 10 min. Thereafter, Mice were perfused with saline and heparin and their brains were harvested and dissected. Brain dissections were homogenized with PBS. Whole brain lysate was precipitated and the fluorescence intensity in each sample was measured.. The results demonstrated a significant decrease in the entry of NaF to the brains of stressed mice in comparison to non-stressed mice. Specifically, mice exposed to 4-weeks UCMS exhibited lower concentrations of NaF in the brain cortex, cerebellum and hippocampus. Mice exposed to 2-weeks UCMS exhibited lower concentrations of NaF in the cerebellum. Mice exposed to acute stress exhibited decreased levels of NaF in the cerebellum and hypothalamus. Whole brain BBB permeability was decreased in 56% following 4-weeks UCMS, 26% following 2-week UCMS and 5% following acute stress. Significant differences in the permeability were shown in the cerebellum, hippocampus, cortex and in other not specific brain area (rest). Based on these findings, it is suggested that stress-induced closure of the BBB in specific brain regions may point to the existence of a protective mechanism in response to stress in which the BBB becomes less permeable to blood circulating substances.
1Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel;
Background: The mechanisms which render an individual susceptible to post-traumatic stress disorder (PTSD) are complex, largely unknown and composed of a dynamic interplay which chiefly involves the hypothalamic–pituitary–adrenal (HPA) axis and its related hormones. Recently, we found that rats which exhibited PTSD phenotype were characterized by blunted amplitude of basal corticosterone (CORT) pulsatility and a blunting of CORT response to stressor. The present study sought to identify the mechanisms that underlie both the loss of pulsatility and the differences in downstream responses. We looked at the neuropeptide arginine vasopressin (AVP) as an important mediator in both CORT pulsatility and PTSD. Methods: Serial blood samples were collected manually via a jugular vein cannula during the (inactive) light-phase in conscious Sprague-Dawley rats at 10-min intervals, immediately before and after exposure to predator-scent stress (PSS). Behaviors were assessed with the elevated plus maze and acoustic startle response tests 7 days later. Brains were harvested for immunohistochemistry. A computer-assisted imaging system was used for quantitative analysis of the density of AVP-ir fibers and cells in the supra-optic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus. In addition, Lewis rats, known for having increased circulating and hypothalamic concentrations of AVP, were used to assess whether these higher levels were correlated with aberrant secretion of corticosterone and PSS-induced impairment of behavioral responses. Results: Rats whose behavior was extremely disrupted (PTSD-phenotype) selectively displayed significant up-regulation of AVP-ir neurons in the PVN and SON, compared to animals whose behavior was minimally or partially disrupted, and to un-exposed controls. Conclusions: The functional alterations of AVP neurons in the hypothalamic nuclei of PTSD-phenotype are of special interest in relation to the impaired regulation of the HPA system
1Tel Aviv University;
Excess release of catecholamines and prostaglandins was shown to mediate pro-metastatic processes of stress and surgery, specifically during the perioperative period. Here, in two randomized placebo controlled clinical trials in colorectal (CRC, n=34) and in breast cancer patients (BC, n=38), we tested the combined perioperative 20-day use of the -blocker, propranolol, and the COX2-inhibitor, etodolac, initiated 5 days before surgery. Tumor samples were collected during surgery, and were subjected to histological analyses, whole genome mRNA profiling, and transcriptional control pathways analyses. In BC patients, 4 blood samples were also collected perioperatively. Drugs were well tolerated. In blood samples, treatment reduced serum IL-6 and CRP levels even before surgery, improved markers of NK cytotoxicity, and enhanced induced production of IFN and IL-12, without affecting anti-inflammatory soluble factors (cortisol and IL-10). In both studies, whole genome mRNA profiling of excised tumors showed decreased epithelial-to-mesenchymal transition (EMT); down-regulation of the transcriptional activity of CREB, NFkB, GATA family, and STAT3; reduced presence of tumor-associated monocytes; and increased presence of NK cells in CRC and B cells in BC tissue. The tumor proliferation marker Ki67 was tested in BC patients, and was significantly reduced by drug treatment. In CRC patients, three-year follow-up showed large but statistically insignificant improvement in disease free survival (DFS) in the treatment group (1/15 vs 5/19), further suggesting the safety of the paradigm. Overall, these findings suggest a critical impact to the short pre-operative period, clearly indicate the efficacy of this combined drug regimen, and suggest its metastatic-reducing impact, which should be tested in larger clinical trials. Such a stress-inflammatory-reducing approach can be exploited during the critical perioperative period, potentially improving long-term survival rates.
1Department of Psychology, Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel, ; 2Chaim Sheba Medical Center, Tel Hashomer, Israel; 3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 4Department of Psychology, Ashkelon Academic College, Ashkelon, Israel;
Objective: Executive functions (EFs), considered essential to coordinate everyday cognitive activity and behavior, have been suggested to be impaired among patients with eating disorders (EDs). EFs may be classified into "cold" EFs, based on sustaining delay to enable data manipulation, and "hot" EFs, coordinating social behavior and emotional reward. Our aim was to evaluate "hot" and "cold" EFs among patients with EDs. Methods: This prospective study included 77 female patients with EDs assessed on admission to inpatient treatment: 50 with binge/purge (B/P) type EDs and 27 with restricting type anorexia nervosa (AN-R). Thirty-four patients with B/P type EDs and 14 with AN-R were reassessed at discharge, when achieving stabilization of weight and disordered eating. Thirty-six matched controls were also assessed twice. "Cold" EFs were evaluated using the Continuous Performance Test (CPT) and the RUFF Figural Fluency Test (RFFT). "Hot" EFs were evaluated using the Emotional Day Night Task (EDNT-ED), modified for patients with EDs. Depression and anxiety were evaluated as well. Results: Patients with AN-R demonstrated difficulties in most CPT parameters, including commission errors and perseverative reactions, both on admission and discharge. Patients with B/P type EDs showed deficient accuracy in various emotional stimulations (happiness, sadness and anger) at baseline as assessed with the EDNT-ED, but better accuracy on the EDNR-ED along with improved RFFT performance at discharge. Conclusions: The findings of his study support a different profile of EF impairment in patients with AN-R and B/P type EDs, both during the acute stage of their illness on admission and following stabilization of weight and disordered eating at discharge.
1Psychology Department, Tel-Hai College; 2Psychology Department, University of Haifa; 3Neurobiology Department, University of Haifa; 4Institute for the Study of Affective Neuroscience (ISAN), University of Haifa; 5Department of Psychology, University of Washington;
The involvement of the amygdala in fear learning is a consensus in the field of neuroscience for decades. In an attempt to extend our knowledge about the amygdala functions in fear, we have tested to what extent amygdala is solely involved in fear conditioning. In a series of experiments we were able to demonstrate for the first time that the amygdala, specifically the BLA, direct both innate and learned fear responses in the rat. Further, we assessed the involvement of other brain regions (beside the amygdala) in contributing to the complex affective valence experienced by animals while encountering negative contextual conditions. We could demonstrate that both negative (BLA) and positive (NAcc)-affect related brain regions undergo plasticity simultaneously to optimize animal behavior under variable environmental conditions. Adding to previous data on top-down modulation of such affective brain circuitry, we found that a bottom-up modulation by the midbrain (dPAG) has a significant contribution. This work presents a system-level approach for addressing the emotional brain dynamic responses to aversive stimuli and to lingering emotional states. The approach revealed functional aspects in emotional systems that could not be studied in the traditional approach which examines separately negative or positive affect systems. These findings leave much to be studied but suggest a method that takes into account the complexity of the emotional brain.
1Tel-Aviv Brüll Community Mental Health Center (Ramat-Chen);
Background: Inadequate prenatal care has been associated with adverse perinatal outcomes. Information regarding compliance of women with different psychiatric diagnoses with specific prenatal tests is lacking. We sought to compare compliance with prenatal care visits (PCV), oral glucose tolerance test (OGTT) and serum alfa-fetoprotein (aFP) in women with psychiatric disorders (WPD) and healthy controls. Method: Subjects were 5,395 women (1,043 WPD and 4,352 controls), members of Clalit Health Services (CHS, Tel-Aviv district, Israel), who gave birth during 2004-2014. We used Generalized Estimating Equations with binary-logistic models, considering consecutive pregnancies as repeated measures with unbalanced design. The diagnostic subgroup was the main independent variable, assessed once with and once without age, socioeconomic status and multiple gestation variables, yielding crude and adjusted odds ratios (cOR and aOR, respectively). Results: There was an increased risk for non-compliance with OGTT in women with depression (aOR=1.4, p=.002, 95% CI=1.1-1.7), schizophrenia (aOR=1.8, p=.01, 95% CI= 1.1-2.9), but not anxiety (aOR p>.40; cOR=1.2, p=.03, 95% CI=1.0-1.6). Women with anxiety were more compliant with aFP than controls (aOR=0.6, p=.001, 95% CI=0.5-0.8). Women with depression and schizophrenia did not differ from controls in compliance with aFP. WPD were at risk for both absence of PCV (aOR=4.6, p<.0005, 95% CI=2.7-8.0) and high utilization of PCV (>20 visits, aOR=2.8, p<.0005, 95% CI=2.1-3.7). Conclusion: WPD tended to under-utilize tests perceived for the wellbeing of the mother (OGTT) and over-utilize tests for the wellbeing of the fetus (aFP). WPD exhibited patterns of both very low and very high utilization of PCV.
1 School of Social Work, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel ; 2Eating Disorders Institution, Psychiatric Division, Rambam Health Care Campus, Haifa, Israel; 3Department of Psychology, Emek Yezreel College, Emek Yezreel, ;
Objective: This study aimed to compare dietary patterns (timing and frequency of binge-eating episodes, caloric intake and macronutrient composition) of patients with binge eating disorder (BED) and bulimia nervosa (BN) with or without Night Eating Syndrome (NES). Design: The study included 59 women (18-60) who sought treatment for Eating Disorders (EDs) and were diagnosed with BED or BN with or without NES. The patients were divided into two groups: NES-BE and BE-only. The participants kept seven-days, 24-hours food diaries and completed demographic and depression questionnaires. Results: patients with NES-BE reported a significantly a higher frequency of binge-eating days and binge-eating episodes during the reported week, and higher energy intake and fat consumption than patients with BE-only. Conclusions: Individuals with NES-BE exhibit higher levels of eating pathology than individuals with BE-only. Thus, NES-BE may not be simply a variant of BED or BN, but rather a separate entity that may lead to a more severe eating disorder. These patients require early assessment and more intensive and suitable treatment alternatives.
1Psychiatry Department, The Chaim Sheba Medical Center, Tel Hashomer; 2The Advanced Thecnology Unit, The Rehaboilitation Hospital, Chaim Sheba Medical ; 3Sackler Faculty of Medicine, , Tel Aviv University, Tel Aviv, Israel; 4The School of Psychology Science, Tel Aviv University ;
Objectives: Several studies have shown an association between panic disorder and vestibular symptoms alongside reduced balance capabilities. These studies were mainly based on balance evaluation questionnaires. The aim of this study was to investigate the postural stability during static and dynamic balance in PD patients using VR and compare the results to the balance evaluation questionnaire that was previously used. Method: Eleven young healthy subjects (age: 31.3±6.3y, 5 women) and 11 young subjects diagnosed with PD (36.9±10.3y, 8 women). All participants were evaluated using psychiatric questionnaires, and assessed for functional balance. Four computerized moveable platform tests were performed: (1) Baseline - standing with eyes open (EO) - (2) as #1 with eyes closed (EC); (3), (4) as #1&2 while performing “serial 7 subtraction” (DT). The order of tests was randomized for each patient. Results: Participants with PD had higher scores on the anxiety level evaluations (more anxiety) and significantly lower scores on the functional balance questionnaires. (DHI: controls 0.09±0.3 PD 5.3±4.4; P=0.0035 and Mini-BEST: controls 31.4±0.9 PD 29.4±2.1; P=0.0186), ABC scores showed a significant difference between PD patients and controls. The dynamic physical measures were not significantly different between the groups. Conclusions: Our results show a significant difference between patients and controls in the anxiety levels and balance questionnaires. However, we found no difference between PD and controls in the static, dynamic and DT physical tests. This shows that PD patients have no objective balance impairment, and tend to subjectively report more balance impairments than normal controls due to their underestimation of self-abilities, a known characteristic of PD patients. Key words: Balance assessment, panic disorder, Virtual Reality.
1Department of Molecular Biology, Ariel University; 2Interdisciplinary Department, Faculty of Social Sciences, Bar-Ilan University; 3C.A.I.R. Institute, The Safdié AIDS and Immunology Research Center, Bar-Ilan University;
Integrin alpha-v-beta3 is a common cell-surface-adhesion receptor expressed in the presynaptic membrane, whose partial deletion was shown to downregulate reuptake of serotonin by SERT. Integrin alpha-v-beta3 has been shown to be functionally inhibited by Ammonium trichloro (dioxoethylene -O,O') tellurate, or AS101. Given the role of serotonergic signaling in regulation of mood and affect, we hypothesized that AS101 may influence pathways regulating anxiety. Thus, we tested AS101 in modulation of anxiety-like behavior using the selectively bred Submissive (Sub) mouse strain. Mice received daily i.p. injection of AS101 (125 µg/kg or 200 µg/kg) or vehicle for 3 weeks, with the injection itself serving as the source of stress, after which their anxiety-like behavior was measured in the Elevated Plus Maze (EPM). Animals were then culled for measurement of serum corticosterone levels by ELISA and hippocampal expression of Brain Derived Neurotrophic Factor (BDNF) by RT-PCR. Chronic administration of AS101 significantly reduced anxiety-like behavior of Sub mice in the EPM, according to both time spent and entries to open arms. At the same time, AS101 markedly reduced serum corticosterone levels of the treated mice, and elevated their hippocampal BDNF expression. Crosstalk between the HPA axis and hippocampal BDNF signaling with the serotonergic systems modulated by AS101 via integrin alpha-v-beta3 and may suggest a mechanism by which AS101 buffers the anxiogenic response to injection stress in Sub mice.
1The Academic College of Tel Aviv Yaffo;
In the 21st century, body image is regarded as a crucial component of psychological health and well-being. The female body ideal has become a focus of research, as it may lead to positive outcomes, such as optimism, self-esteem, and adaptive coping on the one hand, but can also comprise a risk factor associated with depression, stress, and disordered eating on the other. This study investigated the role of fathers as a sociocultural agent for their daughter's body image, focusing on a non-clinical population of young women. The relationship between fathers’ body image perception and their own daughters’ body image perception and satisfaction was examined in forty father-daughter dyads (N = 40). Both fathers and daughters completed the body-image perception measures of the Somatomorphic Matrix (SMM), which includes separate scales for muscle and fat perceptions. Fathers and daughters also completed the Body Esteem Scale (BES). Results showed that the fathers’ perception of attractive women in the muscle dimension positively correlates with their daughters’ satisfaction with their own muscles. Moreover, this correlation is moderated by the fathers’ own body image: it is significant only when the fathers' are satisfied with their own general body image. This pattern of correlations was not found for fat satisfaction measures. The findings demonstrate the importance of including the father, and not just the mother, when considering the parents' influence on their daughters' body image. Furthermore, it should be noted that muscle perception plays a significant role in comprising body image, in addition to fat perception. These finding should be considered by clinicians when seeking treatment for young women suffering, or inclined to suffer, from body image disturbances. Keywords: sociocultural theory, fathers’ body image, daughters’ body image, muscularity.
1Sagol School of Neuroscience, Tel Aviv University; 2Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University; 3Division of Learning Disabilities, Constantiner School of Education, Tel Aviv University; 4School of Psychological Sciences, Gershon H. Gordon Faculty of Social Sciences, Tel Aviv University;
Sexual assault is a frequent interpersonal traumatic experience, which is associated with high susceptibility to PTSD. Nevertheless, and in contrast to other traumatic experiences, studies of brain anatomy in individuals who experienced sexual assault in adulthood have been scarce. Here, we used high-resolution T1- and diffusion-weighted MRI in order to assess alterations in gray matter macro- and micro-structure of key regions implicated in PTSD pathophysiology, namely, amygdala, insula, hippocampus, and anterior cingulate cortex (ACC), in female survivors of adult sexual assault. Thirty-eight sexually assaulted women (PTSD = 25, non-PTSD = 13) and 24 non-exposed matched controls (NEC) were studied. Between-group comparisons revealed decreased volume in the bilateral amygdala and the insula in the PTSD group compared with the non-PTSD group, with no differences in hippocampal and ACC volumes. In contrast, altered microstructural tissue integrity was found in both traumatized groups compared with NEC, including increased mean diffusivity (MD) in the right amygdala, decreased fractional anisotropy (FA) in the right amygdala and hippocampus, and increased FA in bilateral ACC. Conversely, FA in the right insula was increased in the non-PTSD group compared with both PTSD and NEC. Our findings suggest that among adult sexual assault survivors, gross and subtle tissue characteristics of regions involved in PTSD neurocircuitry are distinctively associated with PTSD pathology and stress exposure, as well as with resilience. Our results corroborate the harsh effects of sexual assault, and add to the understanding of the neuroanatomical implications of this traumatic experience.
1Developmental Psychopathology Laboratory, Department of Psychology, University of Haifa;
Behavioral inhibition (BI) is a temperament associated with increased childhood risk for the emergence of adolescent anxiety disorders (AAD). During development, BI children show heightened social reticence, rejection, and anxiety-related behaviors. Classical methods that developmental scientists use to measure BI, entail in-vivo behavioral observation of young children’s social interactions with naive peers or adults. As clinical researchers renew their focus on the critical period of early adolescence, during which the BI risk-factor manifests in psychopathology, it is crucial that valid means for assessing BI during preadolescence. This study includes data on two unique measures of the BI phenotype in preadolescence: the Hebrew Behavioral Inhibition Questionnaire (BIQ) and our novel in-vivo dyadic interaction with a strange adult behavioral observation task (BOS). PART I: The BIQ is a scale that is used to measure BI by means of parent reporting. We produced a Hebrew translation of the BIQ and collected 227 responses from parents of children ages 4 to 15. Results indicated that BIQ demonstrated good internal consistency and test-retest reliability. BIQ also showed convergent validity and discriminant validity. Finally, mother reports of BI were significantly correlated to child reports of BI via the BIQ. PART II: The BOS study is an adaptation of existing behavioral-observation-techniques, to assess BI in dyadic interactions between pre/adolescent participant (ages 8-16 years) and an unfamiliar adult confederate. The protocol was adopted from versions of existing in-vivo behavioral observation paradigms. Specifically, we will be applying a combined protocol based on the get-to-know-you-task (Usher et al., 2015) stranger-situation assessment (Asendorpf, 1987a; G. E. Bishop, 2002). Preliminary data from this ongoing laboratory study will be brought to bear in this discussion for BI assessment during the acute periods of late-childhood and early adolescence.
1Functional Brain Center, Sourasky Medical Center; 2Sackler Faculty of Medicine, Tel Aviv University; 3Sagol School of Neuroscience, Tel-Aviv University; 4Department of Neurobiology, Weizmann Institute of Science; 5Department of Psychology, University of Haifa; 6Division of Mental Health, Medical Corps, IDF; 7School of Psychological Sciences, Tel Aviv University; 8School of Education, Tel Aviv University;
Stress research has progressively become more integrative in nature, seeking to unfold crucial relations between the different phenotypic levels of stress manifestations. This study sought to unravel stress-induced variations in expression of human microRNAs sampled in peripheral blood mononuclear cells and further assess their relationship with neuronal and psychological indices. We obtained blood samples from 49 healthy male participants before and three hours after performing a social stress task, while undergoing functional magnetic resonance imaging (fMRI). A seed-based functional connectivity (FC) analysis was conducted for the ventro-medial prefrontal cortex (vmPFC), a key area of stress regulation. Out of hundreds of microRNAs, a specific increase was identified in microRNA-29c (miR-29c) expression, corresponding with both the experience of sustained stress via self-reports, and alterations in vmPFC functional connectivity. Explicitly, miR-29c expression levels corresponded with both increased connectivity of the vmPFC with the anterior insula (aIns), and decreased connectivity of the vmPFC with the left dorso-lateral prefrontal cortex (dlPFC). Our findings further revealed that miR-29c mediates an indirect path linking enhanced vmPFC-aIns connectivity during stress with subsequent experiences of sustained stress. The correlative patterns of miR-29c expression and vmPFC FC, along with the mediating effects on subjective stress sustainment and the presumed localization of miR-29c in astrocytes, together point to an intriguing assumption; miR-29c may serve as a biomarker in the blood for stress-induced functional neural alterations reflecting regulatory processes. Such a multi-level model may hold the key for future personalized intervention in stress psychopathology.
Obesity is a major health challenge in the modern world as obesity levels increase in an alarming rate. Obesity is mostly attributed to the lack of energy balance in the sedentary modern lifestyle but other factors, primarily the irresistible urge to eat highly-palatable energy-dense food, need to be taken into account. Our and others’ few previous studies show that obesity entails abnormalities in the striatum, a part of the reward system, indicating a potential role for pathology in the reward system in obesity. However, how such abnormalities would expand to downstream structures and translate to overeating is yet to be found. Here we used the diet-induced obesity model to induce obesity in C57 male wild-type mice. After 10 weeks of high-fat-high-sugar diet, we compared the motivation to obtain palatable food and the physiology of ventral pallidum neurons between the top third (obesity-prone) and bottom third (obesity-resistant) weight gainers. We found that obesity-prone mice consistently consumed more calories compared to obesity-resistant mice. After an overnight abstinence from the high-fat-high-sugar diet obesity-prone mice exhibited stronger motivation to obtain high-fat-high-sugar pellets compared to obesity-resistant mice. Interestingly, this difference was not present before the high-fat-high-sugar diet. Lastly, using whole-cell patch clamp electrophysiology we found that ventral pallidum neurons of obesity-prone mice are less excitable and receive stronger inhibitory input compared with obesity-resistant mice. Overall, our data indicates that the pathology in the reward system of obese mice is more widespread than previously thought and includes also the ventral pallidum. This calls for more reward-system-oriented research in trying to understand the underpinnings of obesity in modern society.
1Developmental Psychopathology Lab, Department of Psychology, University of Haifa, Israel;
Fear overgeneralization is a central mechanism in anxiety-related psychopathology. Impaired ability to perceptually discriminate between threat and safety cues is one way through which overgeneralization is hypothesized to occur. A recent study tested a novel discrimination training task in healthy adults in an attempt to improve perceptual discrimination and decrease fear overgeneralization. Results indicated that improved perceptual discrimination was achieved following training which was then translated into improved affective learning (Ginat-Frolich et al., 2017). The current study examined the effects of perceptual discrimination training on fear and extinction learning. Adult participants (n = 56, Mean age=26.6; 73.2% female) were randomly assigned into training or placebo conditions. Pairs of novel geometric shapes were constructed for the training task. In each trial, a target shape from the pair appeared on the screen, followed by a fixation point. Participants were then presented with two shapes and asked to identify the shape that differed from the target. The placebo task used the same shapes, with each shape appearing on one side of the screen. Participants needed to indicate the shapes location. Following this task, an assessment task was administered, and participants were asked whether pairs of a new set of shapes were identical or different. Participants then underwent a differential fear conditioning and extinction task, while self-report and psychophysiological (EMG, SCR) measures were collected. Participants in the training group showed better perceptual discrimination in the assessment task (t(54)=-5.64,p=.000) than did the placebo group. Further, conditioning and extinction were achieved in all measures in both groups (all ps<.016), with the training group displaying less overall fear towards the threat cue than did the placebo group. The results suggest that perceptual discrimination training has some impact on basic fear learning processes.
1Bar Ilan University, Department of Psychology; 2NYU School of Medicine, Department of Psychiatry; 3Hadassah Ein-Karem Medical Center, Jerusalem;
Objectives: Pregnancy Loss (PL) and Stillbirth are recognized as a very difficult life experiences. However, to date, PL research in Israel has been very scarce. This study aimed to examine the prevalence and predictors (socio-demographic, marital and birth-related factors) of Post-Traumatic Stress Disorder (PTSD), Major Depressive Disorder (MDD) and Post-Traumatic Growth (PTG) following PL. Methods: Participants were 99 women, ages 24-49 (M=35.07, SD=5.28), who have experienced PL. The mean pregnancy week of loss was 27.29. 86.7% experienced stillbirth. Participants completed self-report questionnaires assessing birth-related variables, socio-demographics, PTSD (assessed via PCL-5), MDD (BDI), PTG (PTGI), Dyadic Adjustment (DAS) and Dyadic Self-Disclosure (SDI). Results: We have found relatively high rates of both PTSD (32.7%) and MDD (29.6%) among women following PL. High PTSD-MDD comorbidity rates were also found. Interestingly, a negative association was found between the number of previous pregnancy losses and the severity of MDD, perhaps indicating an inoculation process. The number of children a woman had while in the study was negatively associated with PTSD. Both PTSD and MDD were negatively associated with the levels of dyadic consensus, self-disclosure, and affectional expression. Finally, post-traumatic growth was positively associated with PTSD levels, perhaps indicating that finding meaning in one's traumatic experience mostly occurs for those suffering the most. Conclusions: Late PL entails a heavy burden of both PTSD and MDD, presumably since most women at the advanced stages of pregnancy are already strongly attached to their unborn child. The quality of the spousal relationship following PL is an important protective factor. In addition, post-traumatic growth may also occur following PL, as is the case for other studied traumas (e.g., combat). There is a pressing need for novel interventions in both individual and couple's therapy following PL.
1Department of Psychology, University of Haifa;
Individuals display heterogeneous responses to traumatic experiences, including resilience, rapid recovery or development of psychopathology such as posttraumatic stress disorder (PTSD) and depression. Resilience to trauma may be characterized by robust reward function that protects individuals from developing psychopathology. Deficits in reward functioning and anhedonic symptoms are present in about two-thirds of PTSD patients, independent of comorbid major depressive disorder. The endocannabinoid system plays important roles in neuropsychiatric disorders. In a series of studies we have demonstrated that enhancing endocannabinoid signaling after exposure to severe stress prevents PTSD-like (e.g., enhanced startle response, impaired extinction, enhanced negative feedback of the HPA axis) and depression-like (learned helplessness, anhedonia) symptoms. Post-stress endocannabinoid enhancement also prevents plasticity impairments in the nucleus accumbens and hippocampus and the functional alterations of cannabinoid CB1 receptors in the fear circuit (i.e., amygdala, hippocampus and prefrontal cortex). Based on our findings, we suggest that components of the endocannabinoid system are dysregulated in the vulnerability phenotype, and that a resilient phenotype is promoted by enhancing endocannabinoid signaling.
1Ben-Gurion University of the Negev, Department of Psychology, Beer Sheva, Israel ;
Objective: Perceived social support is the most intensively studied resilience factor, yet, research suggests that some individuals do not benefit from it. The aim of this study was to investigate the interaction between the protective effect of social support and personality in terms of psychological and physiological stress responses. Methods: Sixty-five female students completed a battery of questionnaires assessing personality and interpersonal variables, and then arrived to the lab to participate in the study. There, they were randomly allocated to one of two imagery tasks, designed to induce positive support or no support, before being exposed to a standardized psychosocial stressor (Trier Social Stress Test). Physiological stress was measured via heart rate (HR), and time- and frequency-domain heart rate variability (HRV) parameters throughout the procedure. Subjective stress experience was repeatedly assessed before and after stress via anxiety and mood questionnaires. Results: The results show that individual differences moderate the buffering effect of social support. Specifically, we found that an induction of perceived social support reduced physiological stress, but only among individuals with low fear and avoidance of social interactions. We also found that an induction of perceived social support reduced physiological stress, but only among individuals with high levels of attachment anxiety. Conversely, we found an inverse pattern of results regarding self-reported negative mood: participants’ ratings of negative mood were opposite to their physiological stress response. Conclusion: Our results show that the protective effect of social support is altered by individuals’ mental representations and interpersonal relationships. Furthermore, these results are compatible with substantial research demonstrating lack of compatibility between psychological and physiological stress response, raising interesting questions and possible explanations as to the source of this discrepancy.
1Psychology Department, University of Haifa;
Generalization allows for the rapid identification of novel stimuli, but can be maladaptive when occurring in excess. This is the case in fear overgeneralization. Because a deficit in perceptual discrimination is thought to contribute to fear overgeneralization, a perceptual discrimination training task was designed to moderate this mechanism. This study assesses the task’s effectiveness among 73 children (Age range 9-14 yrs). Participants completed a fear-conditioning task, while psychophysiological (SCR, EMG) and self-report measures were collected. Participants were then randomized into three groups: training, placebo and nothing. Pairs of geometric shapes were constructed for the training task. In each trial, a target shape from the pair appeared on the screen (4s), followed by a fixation point (2s). Both shapes then appeared and participants were asked to identify the shape that differed from the target. The placebo task used the same shapes, and participants were asked to indicate which side of the screen the shape had appeared on. Following both tasks, an assessment task was administered comprised of 60 new shape pairs. Participants were asked whether the pairs were identical or different. Finally, a generalization test consisting of 11 morphs (GSs) ranging in perceptual similarity from the CS+ to the CS- was conducted, while self-reported risk assessments and EMG measurements were collected. Successful fear-conditioning was observed in both physiological and behavioral measures (ps<.041). Further, group differences emerged in the assessment task (F(1,46)=4.69,p=.036) with the training group obtaining more correct responses. In the generalization test, differences were observed in EMG trends, with the training group exhibiting better discrimination to the safety cue and additional intermediary morphs. These findings offer preliminary evidence for the effectiveness of the task among children paving the way to assess this task among clinical child populations.
1University of Haifa;
Fear overgeneralization is characteristic of various psychopathologies. Thus, a novel perceptual discrimination training task was designed to moderate fear-overgeneralization. We hypothesized that basic perceptual improvement would enhance discrimination between threat and safety cues. 70 adults completed a fear-conditioning task. Psychophysiological (EMG, SCR) and self-report measures were collected. Participants were then randomized to complete a training or placebo task. Pairs of novel geometric shapes were constructed for the training task. In each trial, a target shape from the pair appeared on the screen (4s), followed by a fixation point (2s). Participants were then presented with two shapes and asked to identify the shape that differed from the target image. The placebo task used the same shapes, with each image appearing on one side of the screen. Participants needed to indicate the location of the image. Following both tasks, an assessment task was administered and participants were asked whether pairs of novel shapes were identical or different. Finally, a generalization test consisting of 11 morphs (GSs) ranging in perceptual similarity from the CS+ to the CS- was conducted. Participants had to assess the risk level of each morph on a 7-point Likert scale. Successful fear-conditioning was observed in both physiological and behavioral measures (ps<.03). Further, group differences emerged in the assessment task, F(1,64)=38.62, p<.001, with the training group achieving more correct responses than the placebo group. In the generalization test, a larger quadratic trend emerged for the training group [estimate=0.1393] than for the placebo group [estimate=0.0790]. Similarly, GSs in the training group were more closely related to the CS- than were those in the placebo group. Both findings indicate better threat-safety discrimination in the training group. These results offer preliminary evidence for the effectiveness of a novel training task on fear learning.
1university of Haifa- The institute of information processing and decision making ; 2;
This research examined the effects of telling a traumatic story in a second language (vs. first language) on stress levels among PTSD participants. It was hypothesized that when a participant’s cognitive resources were invested in formulation of words in a language in which he was not fluent (i.e., the second language), telling the story may become psychologically easier, and stress levels would be reduced. Six participants who had served as combat soldiers in the IDF were recruited for this study. They all reported suffering from PTSD, which was caused by a major event in the army. Participants were recorded individually three times. Data was collected during the interview. The experimental group was recorded first in Hebrew, than in their second language (English) and finally in Hebrew. The control group was recorded in Hebrew in all three instances. Congruent to the research hypotheses, the results indicated an increase in levels of morbidity, intensity, emotional connection and rating of emotional words, and a decrease in filled pauses, number of words per recording, and recording time in the experimental group. Contrary to the research hypotheses, however, the results also indicated an increase in empty pauses, a decrease in number of words per second and no change in the number of emotional words. Overall, using a second language resulted in marginal indication of anxiety reduction in six of the ten measures used. The increase in emotional connection levels in both experimental and control conditions highlights the benefits of merely telling the traumatic story for anxiety reduction, regardless of language use. As a pioneer study, examining the effects of using language on stress levels of PTSD participants, future replications are called for, and may shed light on current results.
1Department of Psychology and the Gonda Brain Research Center, Bar-Ilan University;
Background: Bingeing is the consumption of larger amounts of food in a briefer period of time than would normally be consumed under similar circumstances. In rats, trait binge-eating (BE) like behavior has been characterized by BE prone (BEP) versus BE resistant (BER) behavioral profiles. BEP require palatable food (PF) to trigger an abnormal eating response, probably reflecting a gene x environment interaction similarly observed in human BE. We hypothesized that trait BE (an impulsive-like behavior) will predict the pattern of “conflict behavior”, as assessed by levels of PF eating, given expectation of later negative consequences. Two innovations (1) delayed negative impact (2) internal aversive consequences. Method: 52 female Wistar rats were divided to BER/P eating patterns. Rats from both groups ingested either lactose or glucose, before PF session. Lactose groups were conditioned to anticipate digestive discomfort in association with PF. Procedure included 5 test days, 4 hours each (last test was for long term retention). Each day, PF ingestion was examined over the 4hr period and during the 1st and 2nd 2hr periods. Results: While BERs significantly reduced PF ingestion throughout test days in response to lactose ingestion, this effect was significantly smaller or not evident in BEPs. On test day 5 (no lactose administered), rats previously ingesting lactose reduced PF intake compared to rats previously ingesting glucose, indicating a week-long memory for the lactose-discomfort. This memory inhibited PF feeding by the BER rats only until the discomfort failed to appear after 2hr, representing anticipated “conditioned” abdominal discomfort. In addition, rank order of BE predicted PF consumption in the lactose condition on day 4 at the first and last 2hr and on the first 2hr of day 5. Conclusion: These results support the hypothesis that individual differences in trait BE may reflect and predict individual differences in impulse control and conflict resolution
1Psychology Department, University of Haifa, Israel;
Anxiety disorders are characterized by perturbations in threat learning, which can be examined using fear conditioning paradigms. As an illustration, fear extinction is the basic learning process underlying exposure techniques employed in cognitive behavioral therapy (CBT) for anxiety disorders. Thus, maximizing the effects of extinction learning would assist in treating anxiety disorders. The current study examined whether fear learning is enhanced when participants are more attenuated to conditioned stimuli during extinction. The current data represent 20 healthy adults that thus far participated in this ongoing study. The study used the Screaming Lady fear conditioning paradigm in two visits. In the first visit, participants completed fear conditioning and extinction while self-reports and psychophysiology indices were measured. Participants were randomly assigned to either the experiment group in which they received feedback when gazing directly at the conditioned stimuli’s (CS’s) or to the control group that received no feedback at all. Three days later, participates returned for visit 2 and completed a threat-safety discrimination task comprised of the original stimuli and 2 new stimuli. Preliminary results indicate that participants in the experimental group reported lower levels of fear compared to the controls. Additionally, during the threat-safety discrimination task participants in the experimental group reported lower levels of fear towards the stimuli gradients compared to controls. These initial findings support the premise that attentional processes have an important role in extinction learning.
1Sheba Medical Center, Tel Hashomer, the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 2King’s College, Institute of Psychiatry, Psychology, and Neuroscience London, United Kingdom; 3Singapore General Hospital, 20 College Road, Academia, 169865, Singapore ;
Background: Anorexia nervosa (AN) is characterized by severe malnutrition and intense fear and anxiety around food and eating with associated anomalies in information and emotional processing. Previous studies have found that the neuropeptide oxytocin can influence eating behavior, lower neurobiological stress responses and anxiety, and alter attentional processing of food and eating related images as well as the interpretation and expression of emotions, in patients with AN. Methodology: Thirty adult women with AN and 29 healthy controls (HC) took part in this study. The study used a double blind, placebo controlled, crossover design to investigate the effects of a single dose of intranasal oxytocin (40 IU) on a standard laboratory smoothie challenge, salivary cortisol, anxiety, attentional bias (assessed with an attentional visual probe task), and interpretation and expression of emotions (assessed with the Reading the Mind in the Eyes task, and a video task, assessing expressions of facial affect when viewing humorous and sad film clips). All assessments were carried out before and after the smoothie challenge Results: Relative to placebo, intranasal oxytocin reduced salivary cortisol and altered anomalies in attentional bias towards food images in the AN group. The oxytocin-induced reduction in attentional avoidance of food images correlated with oxytocin induced reduction in cortisol in the AN group before the smoothie challenge. Intranasal oxytocin did not significantly alter subjective feelings of anxiety, interpretation and expression of emotions, or the smoothie intake challenge, in the AN or HC groups. Conclusions: Intranasal oxytocin may moderate automated information processing biases in AN and reduce neurobiological stress. Further investigation of the effects of repeated administration of oxytocin on these processes as well as on eating behavior, subjective anxiety, and interpretation and expression of emotions is of interest
1School of Behavioral Science, the Academic College of Tel-Aviv Yaffo, Tel Aviv, Israel; 2Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3The Dr. Miriam and Sheldon G. Adelson Chair and Center for the Biology of Addictive Diseases, Tel Aviv University,Israel; 4Department of Education and Psychology, The Open University, Ra'anana, Israel;
Anxiety during pregnancy is becoming more prevalent. Adverse events during pregnancy may have negative developmental impact on the fetus. In particular, prenatally stressed offspring are more susceptible to mood disorders throughout their life. The growing rate of depression and anxiety has given rise to greater use of selective serotonin reuptake inhibitors (SSRI) during pregnancy and the post-partum period, although their safety with regards to fetal development is still controversial as the evidence is inconclusive. Contention regarding the use and possible deleterious effects of SSRIs during pregnancy or immediately after has led us to search for alternative herbal treatments. Crataegus pinnatifida was selected from a host of Chinese herbs based on studies showing that it has an anxiolytic and anti-depressive effect, as well as the ability to down-regulate the hypothalamic pituitary adrenal axis and raises monoamine levels in the brain. The study aimed to investigate the effect of prenatal stress on anxiety-like behaviors and brain-derived neurotrophic factor (BDNF) levels in offspring, and to examine whether this effect might be ameliorated by lactation-based escitalopram or herbal treatment. The study was designed to mimic the situation where infants are nursed by mothers treated with SSRIs for post-partum depression/anxiety. To this end, 40 pregnant dams were randomly assigned to either control or restraint stress during the last week of pregnancy. All dams were subjected to treatment (escitalopram, herbal, Vehicle, No-treatment) during nursing (n=5/group). Anxiety-like behavior of dams and offspring (n=317) was evaluated using elevated plus maze and open field tests. Blood and brain samples were collected to assess escitalopram levels in the serum and BDNF levels in the brain. Results indicate that prenatal stress lead to an increase in anxiety-like behaviors among offspring and dams, and these were normalized by either escitalopram or herbal treatment
1Department of Education and Psychology, The Open University of Israel, Raanana, Israel; 2School of Behavioral Sciences, Academic College of Tel Aviv-Yaffo, Tel- Aviv, Israel; 3The Dr. Miriam and Sheldon G. Adelson Chair in Biology of Addictive Diseases, Sackler Faculty of Medicine, TAU, Israel; 4Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel;
Depression and anxiety are highly prevalent and considered of major public health concern worldwide. Selective serotonin reuptake inhibitors (SSRIs), the current first-line treatment for anxiety and depression, are of limited efficacy and slow onset. SSRIs’ clinical response is manifested only after 3-4 weeks of treatment, a period in which symptoms may even be exacerbated. Thus, efficacious fast-onset drugs that will also have sustained effect are in great demand. SSRIs’ delayed onset has been attributed to adaptive regulation induced by serotonin (5-HT) receptors, most notably 5-HT1a. Consistently, complementary treatment with 5-HT receptor agonists or partial agonists was found to expedite SSRIs’ therapeutic outcome. JH is an herbal agent that acts as a partial agonist of 5HT1a receptors and was found to induce anxiolytic-like effects. The aim of the current study was to examine the anxiolytic-like effect induced by the combination between JH and slow-onset conventional and herbal treatments. The herbal treatments are the novel herbal treatment (NHT) and its primary herb, which both have slow-onset anxiolytic- and antidepressant-like activities. ICR mice were exposed to unpredictable chronic mild stress for 4 weeks. Subsequently, mice were treated for 1 or 3 weeks with JH alone or in combination with NHT, NHT’s primary herb, sertraline, fluoxetine or vehicle. Additional groups included treatment with the slow-onset drugs without JH. Anxiety-like behavior was evaluated using the Elevated Plus Maze. Our results indicate that 1-week treatment with JH in combination with fluoxetine, sertraline, NHT or NHT’s primary herb induced fast-onset anxiolytic-like effects. The combination between JH and the slow-onset drugs for 3 weeks did not alter the anxiolytic-like effect induced by individual treatment with the slow-onset drugs. Further analyses in the near future will include assessing 5HT1a receptor in the prefrontal cortex (PFC) and hippocampal BDNF levels.
1BBB-Group, The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel; 2Gonda Brain Research Center, Bar Ilan University, Ramat-Gan, Israel; 3Department. of Education and Psychology, The Open University; 4School of Behavioral Science, The Academic College, Tel Aviv Yaffo; 5The Interdisciplinary Center, Hertzlia, Israel; 6Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY, 10029, ; 7The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel;
The blood-brain barrier (BBB) is a barrier that hinders the entry of most molecules into the brain. Disruption in the BBB can lead to multiple brain pathogenesis. It was demonstrated that frequent BBB disruption in the human cerebral cortex was associated with molecular, clinical, and physiological stress-associated indices. It was also shown that chronic mild stress decreased the activity of superoxide dismutase thereby induces oxidants which in turn disrupts the tight junction proteins of the BBB. In order to test this hypothesis, we used unpredictable chronic mild stress (UCMS) paradigm and detected BBB disruption using sodium fluorescein (NaF) injection. The ICR mice were subjected into four groups, one group with UCMS for one month (N=11), the second with UCMS for two weeks (N=11), the third with acute stress for 30 min (N=14) and control mice (N=10-14). Mice were subjected to one of the stress procedures and then were injected with NaF. Brains were harvested and dissected following perfusion with saline and heparin. The proteins were precipitated using Tri chloric acid and the fluorescence intensity in each sample was detected using a fluorescence plate reader. The results demonstrated significant decreased leakage of NaF in the stressed ICR mice in comparison to control mice. UCMS one month mice group demonstrated decreased leakage of NaF in the brain cortex, cerebellum and hippocampus. UCMS two weeks mice group demonstrated decreased leakage of NaF in the cerebellum. The acute stress group demonstrated decreased leakage of NaF in the cerebellum and hypothalamus. All brain BBB permeability was decreased in 56% percentage following UCMS for one month, in 26% percentage following UCMS for two weeks and in 5% percentage following acute stress. We also found significant differences in the leakage of NaF between the three type of stress in the cerebellum, hippocampus, cortex and in other not specific brain area (rest). These results suggest that the different types of stress cause a gradual resilience of the BBB. As described, mice under chronic and acute stress have less BBB leakage in different brain areas which might indicate a possible protective mechanism for the BBB under stress.
1Sheba Medical Center; 2The Interdisciplinary Center, Herzliya;
Previous research has demonstrated a link between childhood anxiety and sleep problems, but little is known about the link between these difficulties and parental sleep disturbances. Previous studies showed that parents of children with significant sleep disruptions reported decreased mood, parenting stress and fatigue, and parental daytime sleepiness was significantly associated with child's sleep problems. When children experience persistent problems in the process of going to sleep, or when they wake up often during the night, parental attention and active involvement to help the child settle back to sleep is a common strategy to “resolve” the issue. However, research show that this parental behavior often does not lead to a resolution of the problems, and additionally may impact parental functioning. In this context, we conducted a study aimed at exploring the link between anxious children’s sleep difficulties and those of their parents. The results suggested that mothers of children with anxiety disorders exhibited higher levels of sleep disturbances than controls. These difficulties were linked to children's anxiety and sleep problems. When treating children with anxiety, it is therefore important to assess their overall sleep picture, as well as parental sleep difficulties, and when appropriate to add a specific sleep intervention component.
1חוג לפסיכולוגיה, אונ' חיפה;
The role of endocannabinoids in the PFC-accumbens circuit following exposure to severe stress Mizrachi Zer-Aviv T. and Akirav I. Department of Psychology, University of Haifa, Haifa 3498838, Israel Background: Individuals display heterogeneous responses to traumatic experiences, including resilience, rapid recovery or development of psychopathology such as posttraumatic stress disorder (PTSD). The nucleus accumbens (NAc) is known to play a crucial role in reward and a convergence of findings supports a neurocircuitry model of PTSD characterized by abnormally elevated amygdala activity coupled with deficient regulation by the prefrontal cortex (PFC) as well as an abnormal hippocampus. Recent clinical and preclinical studies point to the endocannabinoid (eCB) system as a possible therapeutic target to treat both the emotional and cognitive dysfunctions characterizing this disorder. The transcription factor β-catenin appears to mediate pro-resilient and anxiolytic effects in rodent models for depression and PTSD and there are several reports suggesting that some of the protective effects of the eCB system may be acting on the β-catenin signaling pathway. Materials & Method: Rats were exposed to the shock and reminders model of PTSD, injected with the FAAH inhibitor URB597 (0.3 mg/kg, i.p.) one hour after shock exposure and tested one month after shock exposure for PTSD- and depression-like symptoms or for memory and plasticity in the PFC-NAc pathway. Results: URB597 injected after exposure to severe stress prevented PTSD-like (e.g., enhanced startle response, impaired extinction) and depression-like (learned helplessness, anhedonia) symptoms. Post-stress eCB enhancement also prevented plasticity impairments in the PFC-NAc pathway and the stress-induced decreased sensitivity to reward measured in a water T-maze. Moreover, exposure to severe stress decreased β-catenin levels in the NAc and this reduction was significantly correlated with a resilient response to stress (i.e., reduced startle response and less helplessness following severe stress). Conclusions: The findings suggest that a resilient phenotype is promoted by enhancing endocannabinoid signaling and that this involves interaction with the β-catenin signaling pathway.
1Psychology Department, Bar Ilan University, Ramat Gan, Israel; 2Gonda Brain Research Center, Bar Ilan University, Ramat Gan, Israel;
The prevalence of eating disorder is higher in women compared to men. This difference is reflected in higher incidence, higher risk for health complications and difficulty in recovery in women. Despite many studies on binge eating (BE), there are very few papers that focus on understanding the source of differences between men and women in the tendency towards BE. In order to address this question, we first provide clear distinction between different aspects of eating and eating disorder. Next, we present three potentially mutually compatible explanations for the differences between women and men in BE. We focus on a psychobiological explanation regarding the influence of stress, a biological explanation regarding sex hormones, and a psycho-social explanation regarding objectification theory. We conclude that female gender is a risk factor for eating disorders and BE. A better understanding of the differences between women and men can contribute towards prevention and treatment approaches.
1Geha Mental Health Center, Petach Tikva, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Israel; 3Felsenstein Medical Research Center, Petach Tikva, Israel;
Background: About 30% of schizophrenic patients do not adequately respond to neuroleptics and are defined as treatment resistant schizophrenia (TRS) patients. For decades now, clozapine treatment has been the treatment of choice for these patients. In recent years it has been substantiated that psychotic states influence inflammatory states and vice versa. Previous works have shown conflicting results regarding the effect of clozapine on inflammatory processes and of inflammatory processes on its clinical efficacy. Methods: A retrospective longitudinal study of all adult inpatients admitted under a psychotic state to Geha mental health center (n=97, 169 admissions; age 40.3±10.55 years; 67% male) and treated with clozapine during a 13 year follow-up period. PANSS scores changes and total days of admission were compared for patients with increased or normal levels of inflammatory markers. Excluded were those with chronic inflammatory diseases and/or treated by anti-inflammatory drugs. Results: patients with high neutrophil/lymphocyte ratio (N/L-r>2.5) were found to have increased PANSS-P score on admission (25.0 vs. 21.8, p=0.04). No differences were found following 1 month. Patients with increased CRP levels (>1) did not have different PANSS scores on admission as compared to the rest of the patients. However, after 1 month of hospitalization they displayed no change in PANSS-P scores while the rest did (4.1% vs -12.5%, p=0.014). No difference in hospitalization length was found for either increased N/L-r or CRP levels. Conclusion: These preliminary results expand the knowledge concerning the relationship between the inflammatory and clinical states to TRS patients. In these hard-to-treat patients, N/L-r might serve as an indicator for the severity of psychotic exacerbations and CRP levels may indicate the expected clinical improvement during hospitalizations. Both tests are cheap, simple to perform and readily available.
1Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel ; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Geha Mental Health Center, Petah Tikva, Israel; 4;
Schizophrenia is a chronic debilitating disorder, affecting almost 1% of the general population. Current pharmacotherapy consists of antipsychotic compounds that have an effect mainly on the positive symptoms and to a considerably lesser extent, if at all, on the negative symptoms and the cognitive deficits associated with schizophrenia. About 30-40% of all schizophrenia patients don’t achieve sufficient response to standard anti-psychotic treatment, resulting in a very poor quality of life. Luckily, about 30%-50% of those will response to the drug clozapine. Yet, clozapine-resistant schizophrenia is a major public health problem and represents a subset of patients with the most pressing unmet need for therapeutic options. In our current work we wished to decipher clozapine response mechanisms. We used a pharmacological schizophrenia mouse model and assessed the response to clozapine. The model is based on glutamate NMDA-R antagonism by Dizoclipine (MK-801). After a first analysis of C57/BL mice (G0; N=50 for each sex) response to clozapine, we created four lines of animal responsiveness to clozapine (male/female responsive and male/female resistance). For each generation we used a composite score (CS) of their performance in open field tests (OF). Based on the CS, we selected the most treatment-resistant or treatment-responsive mice (males and females, separately) and used them to propagate the next generation, for five consecutive lineages. Our preliminary data analysis of male sensitive (responsive) mice shows an increment in mice responsiveness to clozapine treatment from 25% in G0 to 58% in G5. The main effect throughout generations was on motility parameters and not on the cognitive ones. Western blot of the frontal cortex shows a trend of decrease in NMDA receptor levels along the generations. This finding supports our previous evidences of glutamate involvement in the response to clozapine.
1Department of Psychology, Bar-Ilan University; 2Gonda Multidisciplinary Brain Research Center Bar-Ilan University; 3Sackler School of Medicine, Tel Aviv University; 4Beer-Yakov and Ness-ziona Mental Health Center;
People suffering from schizophrenia try to cope with immense cognitive difficulties, long after the psychotic episode has occurred. While clinicians today treat schizophrenia mostly with antipsychotic medications, no pharmacological treatment is offered to ease the negative and cognitive symptoms one suffers from. These symptoms, in their various forms, greatly affect the person’s social functioning and may impede his full recovery. Previous studies have supported the beneficial role of minocycline add-on treatment for the relief of positive and negative symptoms, in early-phase schizophrenia, whereas recent focus has been given to explore the medication's effect on cognitive functions as well. Furthermore, minocycline has been examined as a potential modulator in altering social behaviors among healthy individuals. In the current study, we examined whether minocycline treatment can improve symptoms among chronic schizophrenia patients, and whether it can further influence patients' executive functioning and social cognitive skills. We conducted a double-blind pilot clinical trial assessing the feasibility, safety and efficacy of minocycline treatment (200mg/d, 6 weeks) for chronic schizophrenia. Since the clinical study was conducted as a pilot, decisive statistical conclusions cannot be made, though we can observe the trends of results and estimate the potential efficacy minocycline might have in chronic stages of schizophrenia in more extensive studies. We randomly assigned 11 patients to either control (placebo) or experiment (minocycline) groups. Nine patients have completed full participation. Results show patients prescribed with minocycline experienced an improvement in their CGI, PANSS and SANS scores, following treatment. Furthermore, we found higher improvement tendencies among the minocycline group on set shifting and cognitive ToM tasks, but not on empathy measures and other cognitive tasks. Taken together, our results suggest minocycline can be a beneficial add-on treatment for chronic schizophrenia, implying inflammation may still be present in progressed stages of the disorder. Additionally, we observed, for the first time, a potential therapeutic effect of minocycline on social cognitive deficits, associated with the disorder. Our study strengthens previous findings which support the efficacy of minocycline for the treatment of negative and positive symptoms in schizophrenia, and suggests this treatment may also be useful in progressed stages of the disorder.
1Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT, USA; 2Yale University, School of Medicine, Department of Psychiatry, New Haven, CT, USA; 3Mind Research Network, Albuquerque, NM, USA ; 4University of New Mexico, Department of ECE, Albuquerque, NM, USA; 5Central Connecticut State University, Department of Psychological Science, New Britain, CT, USA;
Background: Autism spectrum disorder (ASD) and schizophrenia (SZ) co-occur at elevated rates, and share similar social deficits and genetic risk factors. However, few studies have directly compared these disorders. Dynamic functional network connectivity (dFNC) is a recent analysis method that explores temporal patterns of brain connectivity. We examined dFNC in SZ, ASD and healthy controls (HC). Methods: Resting-state fMRI was collected from 100 individuals: 33 SZ, 33 ASD, 34 HC. High-order independent component analysis (ICA) was performed, followed by dFNC analysis (window=30s, step=1TR, k-means clustering) using the GIFT toolbox. Number of transitions (NT), number of states (NS), fraction time (FT), and dwell time (DT) were calculated per subject. These measures were compared between groups using ANOVA and post-hocs, and correlated with symptoms. Results: Three re-occurring functional connectivity states were identified: 1) cortico-cortical, 2) intra-network, and 3) cortico-cortical with strong visual-sensory-motor connectivity. Compared to HC, both clinical groups showed decreased NS [ANOVA, P=0.001] and increased state-2 FT (SZ were also reduced compared to ASD [ANOVA, P<0.001]), and decreased in state-1 FT [ANOVA, P<0.001]. SZ also showed decreased NT [ANOVA, P<0.001] and state-3 FT [ANOVA, P<0.001], and increased state-2 DT [ANOVA, P<0.001] compared to HC and ASD, and decreased state-1 DT [ANOVA, P=0.001] compared to HC. NT correlated negatively with the positive and negative syndrome scale (PANSS) total score [Spearman, P=0.028; r=-0.282]. Conclusions: Both SZ and ASD demonstrated a pattern of restriction (SZ more pervasive than ASD), specifically being “stuck” in state of weak intra-network connectivity. Differences and commonalities between ASD and SZ were state-specific, and the overall number of transitions between dFNC states correlated with clinical severity.
1Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT, USA; 2Yale University, School of Medicine, Department of Psychiatry, New Haven, CT, USA; 3Mind Research Network, Albuquerque, NM, USA; 4University of New Mexico, Department of ECE, Albuquerque, NM, USA; 5Central Connecticut State University, Department of Psychological Science, New Britain, CT, USA; 6VA Connecticut Healthcare System West Haven, CT, USA; 7Autism And Neurodevelopment Disorders Institute, George Washington University, Washington DC, USA;
Background: Autism spectrum disorder (ASD) and schizophrenia (SZ) co-occur at elevated rates, and share similar social deficits and genetic risk factors. However, few studies have directly compared these disorders. Dynamic functional network connectivity (dFNC) is a recent analysis method that explores temporal patterns of brain connectivity. We examined dFNC in SZ, ASD and healthy controls (HC). Methods: Resting-state fMRI was collected from 100 individuals: 33 SZ, 33 ASD, 34 HC. High-order independent component analysis (ICA) was performed, followed by dFNC analysis (window=30s, step=1TR, k-means clustering) using the GIFT toolbox. Number of transitions (NT), number of states (NS), fraction time (FT), and dwell time (DT) were calculated per subject. These measures were compared between groups using ANOVA and post-hocs, and correlated with symptoms. Results: Three re-occurring functional connectivity states were identified: 1) cortico-cortical, 2) intra-network, and 3) cortico-cortical with strong visual-sensory-motor connectivity. Compared to HC, both clinical groups showed decreased NS [ANOVA, P=0.001] and increased state-2 FT (SZ were also reduced compared to ASD [ANOVA, P<0.001]), and decreased in state-1 FT [ANOVA, P<0.001]. SZ also showed decreased NT [ANOVA, P<0.001] and state-3 FT [ANOVA, P<0.001], and increased state-2 DT [ANOVA, P<0.001] compared to HC and ASD, and decreased state-1 DT [ANOVA, P=0.001] compared to HC. NT correlated negatively with the positive and negative syndrome scale (PANSS) total score [Spearman, P=0.028; r=-0.282]. Conclusions: Both SZ and ASD demonstrated a pattern of restriction (SZ more pervasive than ASD), specifically being “stuck” in state of weak intra-network connectivity. Differences and commonalities between ASD and SZ were state-specific, and the overall number of transitions between dFNC states correlated with clinical severity.
1University of Haifa, Department of Psychology ; 2University of Haifa, Department of Psychology ; 3University of Haifa, Haifa 3498838, Israel;
Increased glutamatergic neurotransmission has been strongly implicated in the pathology of schizophrenia (SZ). Glutaminase1(GLS1) plays a critical role in the recycling of glutamate. Glutaminase1 deficient mice (Gls1+/-) were previously shown to display a SZ-resilient profile, and enhanced learning in the trace fear conditioning task. Here, we aimed to investigate the behavioral profile of Gls1+/- mice in social tasks, i.e., social preference and discrimination. In addition, we asked whether Ebselen, which has recently been identified as a potent GLS1 inhibitor, could mimic the effect of a genetic Gls1 deletion. Finally, we investigated changes in the expression of pre- and post-synaptic markers of glutamate expression in the medial prefrontal cortex (mPFC) in Gls1+/- and Ebselen-treated mice. Ebselen (10 mg/kg) or vehicle were administered for 4 consecutive days to adult wild-type (WT) and Gls1+/- mice. Thirty minutes after the last injection, mice were tested in the social preference paradigm, followed by social discrimination. The mPFC was removed 2 weeks following behavioral testing to assess mRNA expression of the presynaptic markers vesicular glutamate transporter (vGluT1), vesicular GABA transporter (vGAT1), and the postsynaptic NMDA receptor subunits NR1 and NR2A. While no genotypic or drug-induced differences were found in the social preference task, Gls1+/- and Ebselen-treated WT mice showed enhanced social recognition. vGlut1 and vGAT1 were increased in Gls1+/-, but not Ebselen-treated, mice. These findings indicate that a genetically or pharmacologically-induced reduction in Gls1 facilitates social memory, and that the molecular consequences of a constitutive mutation and short-term treatment may be different.
1Psychology Department, University of Haifa, Haifa, Israel; 2Departments of Neurology or Psychiatry, Columbia University College of Physicians & Surgeons, New York, NY, USA; 3Neurobiology Department, University of Haifa, Haifa, Israel; 4Department of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA; 5Department of Cell Physiology and Metabolism, Geneva University Medical Center, Geneva, Switzerland;
Background: Recent findings suggest that glutamate abnormalities underlie hippocampal hypermetabolism in schizophrenia (SZ). Studies measuring cerebral blood volume (CBV) suggest that hippocampal abnormalities occur first in the Cornu Ammonis 1 (CA1) subregion. Insight from glutamate-based animal models supports the role played by glutamate in SZ-related hippocampal abnormalities, but most models focus on the disruption of postsynaptic receptor function rather than on mechanisms that disrupt glutamate homeostasis and release. Aim: Here we set out to identify hippocampal abnormalities at the functional, molecular and behavioral levels, in mice lacking glutamate dehydrogenase (GDH, encoded by Glud1), a mitochondrial enzyme that converts glutamate to alpha-ketoglutarate, in CNS. Methods: Adult male and female CNS-Glud1 deficient (CNS-Glud1-/-) or control (C-Cre+) mice were used in neuroimaging, electrophysiological, molecular and behavioral studies. Results: We found hypermetabolism along with volume reductions specific to right CA1, and elevated glutamate levels in the right hippocampus of CNS-Glud1-/- mice. Sub-regional characterization identified the dorsal right CA1 as principal region of abnormally elevated mRNA expression of both excitatory and inhibitory markers, and a similar pattern of results emerged from mEPSC /mIPSC measurements in the hippocampal slice. These metabolic, molecular and physiological abnormalities were complemented by context learning deficits. Conclusion: Collectively, our results show that Glud1 deficiency phenocopies key features of hippocampal dysfunction in SZ. These findings could provide a novel model of hippocampal dysfunction in SZ, and thus lead to better understanding of SZ etiology and the role played by the hippocampal circuit in the disease.
1Laboratory of Psychobiology, Department of Psychiatry, Rappaport Faculty of Medicine, Technion, Haifa, Israel. ; 2School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel;
Background: Heme, which synthesis involves the mitochondria, had recently gained attention for its role in neurological disorders. Heme oxygenase-1 (HO1), the enzyme responsible for heme’s breakdown, is overexpressed in the substantia nigra of Parkinson's patients, hippocampus and cortex of Alzheimer’s patients, and the prefrontal cortex of Schizophrenia (SZ) patients. In this study we seek to investigate heme metabolism in SZ, and its relation to mitochondrial complex I, which is deficient in SZ. Method: Hemin levels were fluorescently measured in whole cell and in mitochondria derived from SZ and control EBV transformed lymphocytes. ALAS1, peif2a/eif2a and HO1 mRNA and protein levels were analyzed by Western blot and qRT-PCR, respectively. In addition, peif2a/eif2a and HO1 were assessed in 4 brain regions of the Poly-IC animal model of SZ. Lastly, inhibition of complex I was mimicked by the addition of rotenone to control cells and oxygen consumption as well as the above parameters were assessed. Results: Hemin levels were decreased in SZ-derived lymphoblast lysates, with no change in their mitochondria. Protein and mRNA levels of HO1 and the phosphorylation of eif2a, heme downstream target, were significantly increased. ALAS1 did not change. In poly-IC brain, peif2a/eif2a was increased in the Hippocampus and the STR, while decreased in the FC. HO1 was significantly increased in the dorsal hippocampus only. Exposure to rotenone decreased dose dependently mitochondrial respiration at 24 and 48h. Short-term exposure to rotenone caused a dose dependent increase, while longer exposure (48h) caused a decrease in hemin levels. Conclusion: Our data suggests that a decrease in heme may be involved in the pathogenesis of SZ. In addition, we demonstrate that deficits in complex I causes alternations in heme levels in healthy subjects' derived cells, offering a possible link between the two processes.
1Research Laboratory of Psychobiology, Department of Psychiatry, Rambam , Faculty of Medicine, Technion, Haifa, Israel;
Schizophrenia (SZ) is one of the most disabling brain disorders. Abnormalities in dopaminergic transmission and white matter have been documented in clinical studies with SZ patients. An event causality between dopamine (DA) increase and hypomyelination was suggested. Mitochondrial dysfunction has been repeatedly reported in SZ and DA interaction with them as well as its toxic effects on myelin was demonstrated. The aim of this study is to clarify the interaction between dopamine, mitochondria and myelin. Oligodendrocyte cells were grown with medium containing one of three options –DMEM with addition of 10% FCS, biotin or a combination of growth factors including FGF8, IGF, GDNF and BDNF .Differentiation stage of Oligodendrocyte (OLN93) cells, determined by myelin basic protein (MBP) and proteolipid protein (PLP), depends on the media content. Cell grown with 10%FCS stay at their precursor stage, those transferred to biotin+0.5%FCS express significantly more MBP than the precursors, suggesting their differentiation, while cells transferred to medium containing various growth factors, express higher MBP levels and the maturated marker PLP. Drugs interfering with various mitochondrial function, DA, rotenone or cuprizone, affect differentially MBP expression at all differentiation stages. DA highest effect on MBP expression was detected in differentiated OLN93, while rotenone and cuprizone demonstrated a biphasic effect on along differentiation. None of the drugs had an effect on PLP levels. Similarly, mitochondrial various functions, respiration, mitochondrial membrane potential (ΔѰm), cellular distribution and network connectivity, depended on OLN93 differentiation stage. The present study show that interference with mitochondria, alters oligodendrocyte’s myelin major proteins content depending on cell differentiation stage, suggesting mitochondria as a link between myelin and DA
1Laboratory of Psychobiology, Rambam Medical Center, Faculty of Medicine, Technion IIT, Haifa, Israel; 2School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel;
Background: Malfunction of mitochondria, key players in various essential cell processes, has been repeatedly reported in schizophrenia (SZ). Recent studies have reported functional improvement and cellular viability following mitochondrial transplantation in several diseases. Here we aimed to study the effect of isolated active normal mitochondria (IAN-MIT) transfer into the medial prefrontal cortex (mPFC) during adolescence on SZ-related behavior and cellular function in adulthood, using the prenatal immune activation poly I:C rat model of SZ. In this model, the maternal immune response leads to various SZ-relevant deficits in adult offspring. Methods: Pregnant dams were injected with poly I:C or saline. On postnatal days 34-47, their offspring were administered with a single bilateral injection of freshly prepared IAN-MIT or vehicle into the mPFC in a stereotaxic surgery. In adulthood, attentional function was assessed by the latent inhibition (LI) test, and mitochondrial function was evaluated by measuring mitochondrial membrane potential (Δym), cell distribution and network connectivity of animals' fronto-cortical freshly isolated neurons using confocal microscopy of JC-1 stained cells. Results: Medial prefrontal IAN-MIT transfer in adolescence had a prolonged effect on animals behavior and mitochondrial function; it prevented disrupted LI and increased the reduced mitochondrial Δym of adult poly I:C-exposed offspring. However, IAN-MIT transfer did not affect mitochondrial cell distribution and network connectivity. Additionally, control offspring injected with IAN-MIT demonstrated disrupted LI and increased mitochondrial Δym. Conclusion: These findings demonstrate a beneficial effect of IAN-MIT transfer in-vivo, suggesting its therapeutic potential in mitochondrial and brain diseases with bioenergetic and neurodevelopmental abnormalities such as SZ. In addition, this study provides an evidence for a relationship between mitochondrial and attentional functions.
1Psychology Dept., Faculty of Social Sciences, University of Haifa, Haifa, Israel;
Objectives: Alterations in glutamate metabolism play a central role in the pathophysiology of schizophrenia(SZ). Our previous studies point to mice deficient in CNS glutamate dehydrogenase 1 (CNS-Glud1-/- ) mice, which display elevated glutamate release in the dorsal hippocampus, as a novel glutamate-based model of the disease. Disturbance of GABA neurotransmission is one of the hallmarks of SZ, which could be the result of the dysfunction of the GABA synthesizing enzymes GAD65 and GAD67. However, the input of these enzymes in the development of the disease is not well established including their specific localization in the brain regions and functional properties. Methods: We investigated the differential expression of GAD67 and GAD65 proteins in the hippocampus (dorsal vs ventral) and medial prefrontal cortex in CNS-Glud1+/+ (control) and CNS-Glud1-/- mice. We further assessed c-Fos levels in the dorsal hippocampus using immunohistochemical techniques to detect neuronal activation levels following hippocampus-dependent behavior. Results: GAD67/65 ratios were reduced in the dorsal hippocampus of CNS-Glud1-/- mice compared to controls. In the ventral hippocampus, no genotypic differences were found. In control mice, GAD67/65 ratios were lower in ventral compared to dorsal hippocampus. C-Fos activation was lower in CNS-Glud1 -/- mice following trace fear conditioning recollection, compared to control mice. Conclusions: In line with our previous findings, these data highlight the relevance of alterations in hippocampal GABAergic transmission in a mouse model of SZ.
1Research Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center,; 2School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel;
Mitochondria, the main source of energy, also play a major role in Ca2+ buffering in cells. Together with other cellular components, they maintain a constant crosstalk through signaling pathways that modulate transcriptional and posttranslational processes, sustaining protein homeostasis and genome stability in response to varying energy demands and stress. In neurons, which are highly dependent on energy and Ca2+ for their activity, we and others have shown that mitochondria can affect neuronal differentiation, plasticity and neuronal network connectivity all suggested to be impaired in schizophrenia (SZ).Indeed, mitochondrial dysfunction is currently accepted as a pathological factor in this disorder. Here we will further show that transfer of healthy active intact mitochondria (IAN-MIT) into differentiating induced pluripotent stem cells derived from SZ patients improves their mitochondrial function and their differentiation efficiency into glutamatergic neurons. Moreover, transfer of IAN-MIT into the medial prefrontal cortex of Poly I:C rats in adolescence, improves mitochondrial function and restores attentional deficits in adulthood. Notably, in control rats IAN-MIT transfer exerted opposite effects on both parameters, suggesting a linkage between mitochondria and behavior. Our data point at complex I of the electron transfer chain (CoI), as a major cause for mitochondria dysfunction in SZ. Our recent studies show deficits in CoI homeostasis associated with impaired protein levels and function of a core and labile subunit of CoI, NDUFV2. We further show that in SZ samples NDUFV2 pseudogene (NDUFV2P1) plays a role in NDUFV2 deficits. In all, we suggest pseudogene regulation of its parent gene as a cause for mitochondrial dysfunction and thereby for behavioral abnormalities.
Schizophrenia (SZ) and bipolar disorder (BD) are chronic mental disorders characterized by emotional and cognitive abnormalities, which commonly affect young adults. Both disorders share several similarities, including psychotic symptoms, genetic risks, endophenotypes and life-time worldwide prevalence of about 1%. Their pathophysiology is still unclear and the currently pharmacological treatment is decided based on "trial and error" strategy. Numerous studies have shown abnormalities in multifaceted function of the mitochondria in both disorders. Therefore, we aim to identify a mitochondrial based profile as a guideline for personalized treatment, by studying 22 mitochondrial targets of 7 psychotropic drugs in lymphocytes of healthy subjects (in-vitro). We studied 17 different targets, mitochondrial membrane potential (Δψm) mitochondrial cellular distribution and network connectivity as well as levels of 14 mitochondria-related proteins including those involved in the respiratory chain (NDUFV1, NDUFV2, NDUFS1, COX2, SDH1) autophagy (Beclin1, p62) apoptosis (Caspase 3, BAX, BCL2) and mitochondrial network dynamics (OPA1, MFN1, DRP1, FIS1). In an attempt to verify whether drug effects on the mitochondrial parameters in isolated cells can predict treatment outcome, we correlated pretreatment effect of drug in-vitro with its in-vivo effect after a month of treatment to patient. Results: Psychotropic drugs presented a drug specific effect profile on the above mentioned mitochondrial parameters in lymphocytes of healthy subjects (n=28). Drugs affected the parameters similarly in responding patients and controls. In addition, several mitochondrial parameters showed a high correlation between in-vitro and in-vivo response to haloperidol, LiCl and olanzapine before and after treatment, respectively, in patients responding to treatment. Conclusion: Taken together, our findings suggest mitochondrial function as a potential tool to verify individual response to psychotropic medication and thus may facilitate predicting the optimal drug for each patient (personalized medicine).
1Department of Psychiatry, Ruth and Bruce Rappaport Faculty of Medicine, Technion IIT and Rambam Health Care Campus; 2Department of Clinical Biochemistry and Pharmacology; 3Psychiatry Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. ;
Background: Schizophrenia (SZ) and bipolar disorder (BD) are chronic mental disorders characterized by emotional and cognitive abnormalities, which commonly affect young adults. Both disorders share several similarities, including psychotic symptoms, genetic risks, endophenotypes and life-time worldwide prevalence of about 1%. Their pathophysiology is still unclear and the currently pharmacological treatment is decided based on "trial and error" strategy. Numerous studies have shown abnormalities in multifaceted function of the mitochondria in both disorders. Therefore, we aim to identify a mitochondrial based profile as a guideline for personalized treatment, by studying mitochondrial targets of 7 psychotropic drugs in lymphocytes of healthy subjects (in-vitro). We studied mitochondrial membrane potential (Δψm) mitochondrial cellular distribution and network connectivity as well as levels of 14 mitochondria-related proteins including those involved in the respiratory chain (NDUFV1, NDUFV2, NDUFS1, COX2, SDH1) autophagy (Beclin1, p62) apoptosis (Caspase 3, BAX, BCL2) and mitochondrial network dynamics (OPA1, MFN1, DRP1, FIS1). In an attempt to verify whether drug effects on the mitochondrial parameters can predict treatment outcome we correlated pretreatment effect of drug in-vitro with its in-vivo effect after a month of treatment to patient. Results: Psychotropic drugs presented a drug specific effect profile on the above mentioned mitochondrial parameters in lymphocytes of healthy subjects (n=28). Drugs affected the parameters similarly in responding patients and controls. In addition, several mitochondrial parameters showed a high correlation between in-vitro and in-vivo response to haloperidol, LiCl and olanzapine before and after treatment, respectively, in patients responding to treatment. Conclusion: Taken together, our findings suggest mitochondrial function as a potential tool to verify individual response to psychotropic medication and thus may facilitate predicting the optimal drug for each patient (personalized medicine).
1Technino-Israel Institute of Technology;
Our laboratory has been studying the neurobiology of D-serine, a D-amino acid which is increasingly appreciated as an important transmitter/signaling molecule. D-Serine modulates N-methyl D-aspartate receptors (NMDARs) and regulates synaptic plasticity, neurodevelopment, and learning and memory. However, the primary site of D-serine synthesis and release remains controversial, with some arguing that it is a gliotransmitter and others defining it as a neuronal cotransmitter. Recent controlled experiments demonstrate that the biosynthetic enzyme of D-serine, serine racemase (SRR), is expressed almost entirely by neurons, with few astrocytes appearing to contain D-serine. Instead of producing D-serine, we found that astrocytes mainly export L-serine to neurons to fuel the synthesis of D-serine by the neuronal SRR. This metabolic cross-talk, called "serine shuttle", appears to be the main determinant of D-serine production, and possibly glycine levels as well. Genetic studies and knockout mice models now implicate six serine shuttle genes (PHGDH, PSAT1, SLC1A4, SLC7A10, SRR and DAO) in severe neurological problems, mental disability, and in neuropsychatric disease as well. In particular, SRR is one of the 108 chromosomal loci associated with schizophrenia in a large genome wide association study, and patients with schizophrenia display lower D-serine in CSF. We will present results on how the serine shuttle differentially regulates the synthesis of D-serine and glycine and affects NMDAR synaptic plasticity, and learning and memory.
1Interdisciplinary Center Herzliya (IDC); 2Weizmann Institute ; 3Shaar Menashe Mental Health Center; 4Geha Mental Health Cente;
TMS-responses as measured by EEG show a higher trial-to-trial variability in schizophrenics than in controls (Ferarrelli et al. 2008, Frantseva et al. 2014). However, the factors that contribute to this variability are unclear. This talk will present a large TMS-EEG study with 18 patients and 29 controls, each repeated 3 times, across three weeks. Background activity was characterized and various features based on the instantaneous phase and amplitude in different frequency bands were extracted. While in the literature the differences observed between SCH and HC are attributed to alterations in the dynamics of the TMS-evoked responses, our findings suggest a second contribution that originates from alterations in ongoing activity, which can also explain previously reported response variability and is consistent with other ERP studies. Implications to EEG studies will be discussed.
1Tel Aviv University;
Schizophrenia is a neurodevelopmental disorder manifested symptomatically after puberty. The recognition that the formal diagnosis of the disorder is preceded by progressive behavioral and neuropathological abnormalities, has kindled an interest in preventive interventions during this "prodromal" period. Clinical studies indicated that atypical antipsychotic drugs (APDs) may reduce risk of progression to first-episode psychosis, but results are controversial. Novel interventions based on pathophysiological mechanisms believed to play a role in schizophrenia such as inflammation and redox dysregulation, are heavily advocated but studies in humans are challenging. Valid animal models of schizophrenia are imperative in this context. Here we used the maternal immune activation (MIA) model which is based on the known association between maternal infection in pregnancy and increased risk of schizophrenia, to test the efficacy of early intervention with two compounds with strong anti-inflammatory and anti-oxidant properties, Omega 3, and N-acetylcysteine (NAC). Offspring of pregnant dams injected on gestational day 15 with the viral mimic poly-I:C or saline, were treated in adolescence (postnatal days [PND] 22-47) with either ω-3 PUFAs- enriched diet or NAC at 900 mg/l in drinking water, and tested in schizophrenia-relevant tasks in adulthood (PND>90). Prenatal poly-I:C led to deficits in selective attention and executive function as indexed by disrupted latent inhibition (LI) and abnormally rapid reversal. Both behavioral abnormalities were prevented by omega3 whereas NAC was partially effective. These results support the notion that anti-inflammatory/anti-oxidant compounds, which may be more benign than APDs, have a potential to prevent the emergence of behavioral abnormalities following prenatal insults.
1Behavioral Neurogenetics Center, Sheba Medical Center & Sagol School of Neuroscience, Tel Aviv University; 2International 22q11.2DS Brain and Behavior Research Consortium (IBBC 22q11.2DS);
Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a full-blown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (ages 6–55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites worldwide, as part of an international research consortium. Of them, 692 were non-psychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13–25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants’ subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population.
1Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 2Behavioral Neurogenetics Center, The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer; 3Felsenstein Medical Research Center, Tel Aviv University; 4George S. Wise Faculty of Life Sciences, Tel Aviv University;
Background: 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic disorder, characterized by high rates of medical comorbidities, immune system abnormalities, psychiatric disorders and cognitive deficits. The aim of our study was to explore sleep quality in 22q11.2DS and its association with psychiatric disorders, medical conditions, immune abnormalities and cognitive deficits. Methods: We assessed sleep quality in 35 22q11.2DS individuals (among them 8 with psychotic disorders and 27 without psychotic disorders) compared to 26 typically developed controls using the Pittsburgh Sleep Quality Index (PSQI). Results were correlated with clinical data, cytokines levels and cognitive functioning. Results: We found that 22q11.DS participants had significantly higher PSQI scores (i.e., worse sleep quality) than controls. This difference remained significant when psychotic 22q11.2DS participants that were on medications that affect sleep quality, were excluded from the analysis. For the non-psychotic 22q11.2DS participants, PSQI scores (total score, latency score and day time sedation) were positively correlated with circulatory interleukin 6 levels and negatively correlated with cognitive functioning. The association between sleep quality and several medical and psychiatric disorders was assessed, but no additional associations were found. Conclusion: We have demonstrated that 22q11.2DS individuals have multiple sleep disturbances. In the non-psychotic 22q11.2DS group interleukin 6 levels was inversely correlated with sleep quality and cognitive functioning, two factors that were previously associated with psychosis in 22q11.2DS.
1Dept. of Psychology, University of Haifa ;
Glutamate is the most prevalent excitatory neurotransmitter in the central nervous system, and is involved in basic sensory as well as higher cognitive functions. The glutamate synapse is complexly regulated by pre-synaptic, post-synaptic and glia-controlled processes. Glutamate abnormalities are implicated in several CNS disorders, including schizophrenia, depression and epilepsy. The glutamate hypothesis of schizophrenia stems from the fact that noncompetitive blockers of the glutamate NMDA receptor induce schizophrenia-like symptoms in healthy individuals, and several lines of evidence point to abnormal glutamate levels in the prefrontal cortex and hippocampus of afflicted individuals. Animal models can be used to gain better understanding of mechanisms underlying glutamate abnormalities in schizophrenia. Data emerging from animal studies support the role played by abnormal glutamate transmission in schizophrenia-related symptomatology and pathophysiology, and point to glutamate-driven hippocampal hyperactivity as the driver of psychosis, Furthermore, recent studies may identify novel pathways of psychopharmacological intervention targeting the glutamate synapse.
1Laboratory of psychobiology, Ruth and Bruce Rappaport Faculty of Medicine, Technion IIT ; 2Department of Psychiatry, Rambam Health Care Campus; 3Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University; 4Beer-Sheva Mental Health Center;
One of the theories regarding the pathogenesis of mental disorders is mitochondrial dysfunction. In addition, mitochondria are affected by many psychotropic drugs. During my "basic science" training, I tested mRNA expression of 14 mitochondrial genes in 11 healthy control subjects as part of a larger study that examined many differences in mitochondrial parameters between treated and untreated control samples. The effects of psychotropic drugs on mRNA expression in control subjects together with the data obtained about other mitochondrial parameters will enable us to create a "profile of effect" for each drug. Those profiles will be used in a following research, which will compare gene expression in patients who responded or failed to respond to a drug in order to identify parameters that predict response to treatment. During my training I took blood sample from the subjects, Isolated the lymphocytes, incubated the cells with the drugs, extracted the mRNA, used qRT-PCR in order to compare different gene expression with and without various drugs and analyzed the results. mRNA expression failed to show a significant difference between treated and untreated samples in line with previous finding of short-term antipsychotic drug and mood stabilizer treatment. In a parallel study, protein levels of the same genes were examined and there were significant differences. This might indicate that the effect of the psychotropic drugs is in the post-transcriptional stage.
1University of Haifa, Psychology Dept.;
Background: Most neurotransmitter glutamate is recycled through the glutamate–glutamine cycle, in which phosphate-activated glutaminase 1 (gene GLS1) converts glutamine to glutamate in neurons. Mice with a targeted disruption of a single copy of the Gls1 gene (GLS1 hets) show a mild reduction in glutamate in several brain regions including the hippocampus and frontal cortex, and are insensitive to the effects of amphetamine, a dopamine agonist which induces a psychosis-like state typically characterized by paranoid delusions. NMDA receptor hypofunction engenders schizophrenia(SZ)-like symptomtology in healthy humans and animal models, and leads to excessive glutamate release. Moreover, neonatal NMDAR blockade, which mimics a neurodevelopmental disruption hypothesized as central to SZ etiology, phenocopies key aspects of SZ in rodents. It is unclear whether GLS1 hets are resilient to early developmental manipulations, and specifically to neonatal NMDA receptor blockade. Aim: We investigated SZ-like behavioral deficits in adult male and female GLS1 hets and their wild-type (WT) controls, following neonatal administration (PND 6-10) of the NMDA receptor antagonist MK-801 (0.1 mg/kg) or saline. Our behavioral battery included locomotor activity in Open Field (OF), the object location task (OLT), the Novel Object Recognition task (NOR), social preference, and reversal learning in the Water T-maze. Results and Conclusion: Our results indicate that neonatal NMDA receptor blockade induces SZ-like behavioral abnormalities in WT, but not GLS1 het, mice. These findings provide further support for the potential of inhibiting GLS1 as a novel treatment strategy for some SZ symptoms.
1University of Haifa, Department of Psychology;
Background: Increased glutamatergic neurotransmission has been strongly implicated in schizophrenia (SZ). Glutaminase 1 (GLS1) plays a critical role in glutamate recycling. Previous studies show that mice with a constitutive genetically induced deficit in the Gls1 gene (Gls1+/- mice) have a SZ-resilient profile, display reduced glutamatergic activity in the hippocampus and an attenuated response to the acute and chronic effects of dopamine-releasing psychotomimetic drug amphetamine. A recent study identified Ebselen as a potent GLS1 inhibitor. Aim: We analyzed the effects of repeated Ebselen treatment on amphetamine sensitization. Results: Ebselen-treated mice showed reduced GLS1 expression in the hippocampus and a trend towards an attenuated response to amphetamine sensitization. Amphetamine sensitization led to an increase in the mRNA expression of dopamine receptor 2 (D2R), but not dopamine receptor 1 (D1R), in the ventral striatum of WT mice, but had no effect on D2R expression in Gls1+/- mice. Interestingly, Ebselen-treated amphetamine sensitized mice displayed significantly higher levels of striatal D1R and D2R mRNA. Conclusions: GLS1 plays a critical role in regulating dopamine activity subsequent to amphetamine sensitization. The attenuated behavioral response to amphetamine sensitization may stem from differential molecular pathways of action in Gls1+/- and Ebselen-treated mice.
1University of Haifa, Psychology Dept.;
Dysregulated glutamatergic neurotransmission has been strongly implicated in the pathology of schizophrenia (SZ). Glutaminase 1 (GLS1) plays a critical role in the recycling of glutamate. GLS1 deficient mice were previously shown to display an attenuated response to the acute and chronic effects of the dopamine-releasing psychotomimetic drug amphetamine. A recent large-scale drug screening study identified ebselen as a potent CNS-available GLS1 inhibitor. Here, we asked whether ebselen (10 mg/kg) would attenuate sensitization to amphetamine (4 mg/kg). Adult 129SVe mice were divided into 4 experimental groups, and received i.p. injections on 4 consecutive days (sensitization) and 7 days later (challenge): SAL-SAL, SAL-AMPH, AMPH-AMPH, AMPH+EBS-AMPH+EBS. We found decreased sensitization to amphetamine in mice that received pre-treatment with ebselen. Ongoing gene expression studies are performed to assess reduction of GLS1 transcripts and altered expression of dopamine markers in the striatum.
1Lev Hasharon MHC;
Religious and spiritual beliefs play a major role in the life of many patients with psychiatric disorders. According to the scientific literature, Religious/spiritual beliefs, as well as the spiritual well being of an individual, are a positive prognostic factor in coping with these psychiatric disorders. Nevertheless, the professional teams (psychiatrists, psychologists ecc.) who take care of these patients, are often not paying enough attention to the "spiritual/religious world" of their patients. The goal of this research was to describe the religious/spiritual beliefs among people with psychiatric disorders, and to examine the correlation between these beliefs and the clinical state of the individual. Another goal of the research, was to examine the level of interest, that the professional teams showed in the "spiritual/religious world" of their patient. The results of the research showed a high percentage of psychiatric patients, who believe in some kind of a religious/spiritual belief. The results also showed a negative correlation, between the level of spiritual/religious belief, and the severity of depressive symptoms, psychotic symptoms and suicidality. Another result was a positive correlation between the "spiritual well being" of an individual and his "general quality of life". Another finding was that professional teams, showed a low level of interest in their patients "spiritual/religious world".
1Geha Mental Health Center, Petach-Tikva, Israel; 2Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel; 3Psychosis Studies Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK;
More than 100 years of research of schizophrenia and the precise mechanism of the underlying brain pathology is yet to be deciphered. Moreover, the therapeutic targets are still very much symptomatic and probably address downstream sequels of the main site of nueropathology. The key to make some progress , scientifically and eventually clinically, might by in breaking up the clinical syndrome into several distinct biological processes, each with its own pathological pathway and appropriate therapeutic intervention. in the presentation we will look into future directions of making more precise diagnostic decisions leading to personalized targeting of medication.Precision in psychiatry and in schizophrenia specifically is becoming mandatory to help and support patients suffering from the more severe forms of schizophrenia.
1Department of Psychiatry, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel; 2Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.; 3Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; 4Department of Psychiatry and Department of Preventive Medicine,Icahn School of Medicine at Mount Sinai,New York, NY, USA; 5IDF Medical Corps, Israel.; 6Department of Psychiatry,Rambam Medical Center,Technion-Israel Institute of Technology,Haifa, Israel.; 7Department of Mental Health, Ministry of Health, Israel.;
Understanding the association between advanced paternal age and schizophrenia Marina Belyak1, MD, Daphna Fenchel1, MSc, Eyal Fruchter5,6, MD, Shimon Burshtein1, MD, Ariel Ben Yehuda5, MD, Rinat Yoff7, MA, Abraham Reichenberg4, PhD, Michael Davidson1,2, MD, Sven Sandin PhD 3,4, Mark Weiser1,2, MD 1Department of Psychiatry, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel. 2Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 3Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden. 4Department of Psychiatry and Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 5IDF Medical Corps, Israel. 6Department of Psychiatry, Rambam Medical Center, Haifa, Israel; Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. 7Department of Mental Health, Ministry of Health, Israel. Importance: Previous studies suggest an association between advanced paternal age at birth and risk of schizophrenia. Some investigators have hypothesized that this association is caused by older fathers having more replications of sperm cells and therefore more mutations over time, while others have linked this association to psycho-social and/or genetic characteristics of older fathers. Objective: To examine these competing hypotheses and to understand if this association is due to de novo mutations, characteristics of older fathers, or both. Design: Historical prospective population-based cohort study. Setting: Adolescents assessed by the Israeli army draft board prior to induction into military service and followed for later psychiatric hospitalization. Participants: 920,783 subjects screened in the draft boards of the Israeli Defense Force, with complete data on parental age at birth and socio-economic status (SES). Main Outcomes and Measures: ICD-10 diagnoses from the national psychiatric hospitalization case registry of narrowly defined schizophrenia (F20.0-F20.9) with follow-up up to 30 years after screening by the draft board. Results: A total of 4502 (0.5%) were hospitalized for schizophrenia. In the entire population, paternal age at birth was associated with increased risk of schizophrenia: OR=1.02, 95% CI=1.01-1.03, adjusted for maternal age at birth and SES. Compared to a reference group of paternal age of 25-29 at birth, paternal age of 45 or older at birth was associated with increased risk of schizophrenia: OR=1.58, 95% CI=1.32-1.88, adjusted for maternal age at birth and SES. Advanced paternal age at birth of first child was associated with increased risk of schizophrenia (adjusted OR=1.09, 95% CI=1.07-1.10). When taking into account paternal age at birth of first child, advanced paternal age at birth was not associated with increased risk of schizophrenia (OR=0.94, 95% CI=0.93-0.96). No associations between advanced paternal age at birth and risk of schizophrenia were found when controlling for sibship. Conclusions: Our data does not support the hypothesis that de novo mutations are behind the association between advanced paternal age at birth and schizophrenia, but instead support a role for psycho-social and/or genetic factors of older fathers.
1Geha Mental Health Center, Petah-Tikva, Israel; 2Interdisciplinary Center Herzliya; 3Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; 4Sacker Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel; 5Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Petah-Tikva, Israel; 6Psychosis studies department, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, UK;
Schizophrenia is a chronic disorder which results in impairment of daily function and therefore causes a dramatic suffering and reduction in quality of life to those who have it and their families. Clozapine, the first atypical, second generation antipsychotic, is the best (and only) available treatment to those who are unresponsive to other antipsychotics. However, 40% to 70% of patients will remain highly symptomatic even with clozapine therapy. Novel research suggests that vitamin D has an effect on the brain, and hypovitaminosis D is associated with psychopathologies, including schizophrenia. Further studies, testing the correlations between vitamin D and specific symptoms’ domains in schizophrenia, yielded insufficient evidences. The current study explored the association between levels of vitamin D and level of symptoms: positive, negative and depressive symptoms, cognitive function and metabolic profile, among people with residual schizophrenia, treated with long-term clozapine. The study was conducted in "Geha" Mental Health Center, and recruited 47 participants from the hospital inpatients units and ambulatory services. All participants had a diagnosis of schizophrenia, with significant level of symptoms as estimated by the Positive and Negative Syndrome Scale (PANSS) score above 70, and the Clinical Global Impression Scale (CGI) score above 3. After signing the consent form, vitamin D level was measured, and symptoms level was evaluated. Analysis included two types of group partitions based on the vitamin D level: the first was to three groups based of deficiency categories: deficient vitamin D level (less than 25n/mol), insufficient level (25-50 n/mol) and sufficient level (more than 50n/mol). Second partition to tertiles (i.e three equal groups), in which the first group was composed of those with the lowest levels in the sample, the second group the mid-levels and the third group the highest levels of vitamin D in the sample. One Way Analysis of Variance (ANOVA) was used to test differences between the groups in the symptoms level. In addition, Pearson’s and Spearman's correlation were tested between vitamin D level and different symptom domains. Significant differences were found between the tertiles partition in the general level of symptoms (PANSS total) and cognitive function. There were no significant differences in other variables and in the deficiency grouping. No significant Pearson/Spearman's correlations were found. We concluded that among people with residual symptoms of schizophrenia, treated with clozapine, higher levels of vitamin D are associated with lower level of symptoms and better cognitive function. These results may indicate a new and safe therapeutic approach for maximizing treatment in this severely ill population.
Traumatic Brain Injury
1Department of Anxiety and Stress Research Unit, Beer-Sheva Mental Health Center, Ministry of Health, Israel. ; 2Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel. ; 3Department of Mechanical Engineering Ben-Gurion University of the Negev, Beer Sheva, Israel.; 4Department of Clinical Biochemistry, Soroka University Medical Center, Beer Sheva, Israel.;
Blast wave-induced minimal traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) have become one of the most frequent injuries in the military and civilian health care sectors since the increase in worldwide terrorism and warfare. Those injuries tend to become chronic injuries in the absence of early diagnosis and intervention. Accurate diagnosis and the initial care of those injuries are a complex challenge especially in the events of mass casualties, and may led to delay the necessary therapeutic intervention. Therefore, early identification of the affected population is of great clinical importance for treatment planning, and rehabilitation assessment for patients. In this study, we determined the levels of CFD in serum at different intervals after low-pressure blast wave exposure to evaluate its potential utility as a sensitive biomarker of blast-induced (psycho)pathology. Our hypothesis was that CFD levels correlate to the behavioral response patterns, and thus may predict the outcome of blast-wave injured. Non-anesthetized rats were exposed to visual, auditory, olfactory, low pressure blast-wave. Blood was obtained from the rats by sublingual puncture under Isoflurane-anesthetized. Simultaneously, combining of cognitive and behavioral paradigms were used in order to determine the rats' performance. The results showed that blast exposure caused significant time-dependent increases in serum CFD at 2 h post-exposure and was independent of the psychopathology. For most of the rats, the maximum increase was recorded at 2 h, and CFD levels returned to baseline by 5 h post exposure. In rats displaying PTSD-phenotype or mTBI-phenotype, the maximum level of circulating CFD was observed at 2 h post exposure and was still significantly elevated at 5 h after blast exposures, likely indicating a slow clearance after a transient release of CFD into the circulation. CFD levels may be used as a marker to assess psychopathology after blast exposure.
1Tel Aviv University, Anatomy, Tel Aviv, Israel;
Traumatic brain injury (TBI), a brain dysfunction for which there is no present effective treatment, is often caused by a concussive impact to the head. The impact of diet on brain function and susceptibility to neuropsychiatric and neurodegenerative disorders is increasingly appreciated. In addition, rodents maintained on dietary restriction (DR) perform better on learning tasks than do rodents fed ad libitum (AL). Here, we demonstrate a neuroprotective effect of DR in a mouse model of induced mild TBI (mTBI). Mice were divided into two main groups following a weight drop (30, 50 and 70gr). AL group was fed normally while the DR group was maintained on an alternate day feeding regimen. Cognitive and behavioral performance was assessed 30 days post injury using the Novel Object Recognition (NOR) and the Elevated Plus Maze (EPM) tasks. Results taken from the NOR task show that all groups of mTBI mice (30,50 and 70 gr) maintained on normal diet were significantly impaired post injury compared with the no- mTBI (p<0.03, p<0.001 and p<0.001 respectively) and the mTBI+DR groups (p<0.01, p<0.001 and p<0.007). EPM analysis shows no difference between all groups, indicating that injury failed to cause any anxiety like behavior. Currently we are examining the role of Sirtuin1 in this neuroprotective mechanism, as it is known to have a key role in the biological effect of DR. These results bolster accumulating evidence that DR may be an effective approach for increasing the resistance of the brain to damage.
1Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; 2Department of Anxiety and Stress Research Unit, Beer-Sheva Mental Health Center, Ministry of Health , Beer Sheva, Israel; 3Department of Mechanical Engineering Ben-Gurion University of the Negev, Beer Sheva, Israel;
Background: The complex interactions and overlapping symptoms of comorbid posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) induced by an explosive blast-wave have become a focus of attention in recent years. Although behavioral and epidemiological research has advanced our understanding of the clinical manifestations of PTSD and mTBI, less is known about the underlying neural mechanisms. The present study sought to identify molecular and morphological properties related to PTSD-phenotype and mTBI-phenotype. Methods: Non-anesthetized animals were exposed to visual, auditory, olfactory, and tactile effects of a controlled experimental explosive blast-wave. Validated cognitive and behavioral paradigms were used to assess behavioral and cognitive changes. Neurons from several brain regions were reconstructed and subjected to Sholl analysis . GR, BDNF, NPY, GFAP, Tau protein, NLRP1 and NLRP13 inflammasome were evaluated in the hippocampus. Data for individual rats were analyzed in correlation with retrospective classification into behavioral/cognitive response groups. Results: Some of the molecular changes observed in blast-induced mTBI-phenotype were also observed in PTSD-phenotype such as decreased BDNF, NPY (markers for plasticity damage), and increased GFAP, NLRP1, and NLRP3 (markers for inflammation). An elevation in the expression of tau protein in the hippocampus was observed in mTBI-phenotype. In addition, exposure to blast-wave elicited distinct morphological responses associated with mTBI-, PTSD-, and comorbid mTBI-PTSD-phenotypes. Conclusions: We suggest that blast-induced mTBI-phenotype alters the fear/anxiety neurocircuitry on the neuro-molecular level. Although we found an overlapping in some signaling pathways related to plasticity and inflammation, we assume that the differences in patterns of neuronal and morphological between PTSD- and mTBI-phenotypes may reflect distinct underlying biological profile.
1Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 2Translational Gerontology Branch, IRP/NIA/NIH , Baltimore, Maryland, USA; 3Department of Chemistry, Indiana University, Bloomington, Indiana, USA; 4Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, USA;
Traumatic brain injury (TBI) is a pressing public health concern with no specific therapeutic treatment. Mild TBI (mTBI), which accounts for approximately 90% of all TBI cases, may frequently lead to long-lasting cognitive and behavioral impairments. The incretins: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal hormones which mainly regulate insulin secretion. Mimetics of these peptides have shown neuroprotective properties in animal models of Parkinson's and Alzheimer's disease. The aim of the present study is to evaluate the potential benefit of enhancing the incretin activity in the brain following mTBI by using two different drugs: liraglutide (GLP-1 analogue) and twincretin (dual GLP-1R/GIPR agonist). To do so, we subjected mice to mTBI using a weight-drop device and administered liraglutide or twincretin in a 7-day regimen of SC injections. Subsequently, we investigated the effects of these drugs on cognitive impairments, neuronal degeneration and neuroinflammation following mTBI over several times. Both drugs ameliorated mTBI-induced visual and spatial memory impairments as assessed by the novel object recognition and the y-maze paradigms, respectively. No differences between groups were evident in anxiety-like behavior as assessed by the elevated plus maze. Both treatments significantly mitigated mTBI-induced neuronal degeneration as was quantified by immunohistochemical staining of Fluoro-Jade B and anti-NeuN antibodies. MTBI resulted in elevated astrocytes and microglia count as was evaluated by GFAP and Iba-1 imunno-staining respectively. No treatment affected the astrocyte-elevation. However, liraglutide and twincretin significantly reduced the mTBI-induced elevation of microglia. These findings offer a new potential therapeutic approach to treat mTBI. Further studies will continue to investigate the neuroprotective effects and mechanism of action of incretin-based therapies within the brain.
1Schneider Children’s Medical Center of Israel, Petach Tikvah, Israel; 2Department of Psychology, The Hebrew University of Jerusalem, Israel; 3;
Background: Mild Traumatic Brain Injury (mTBI) has become a major public health problem; Children are being exposed to various forms of head injury which are common reasons for hospital emergency room presentation. M-TBI is a leading cause of Post-Concussion syndrome (PCS) manifested by sustained physical, cognitive, emotional, and behavioral symptoms in children, adolescents and adults. Although most children who are victims of m-TBI usually recover from the symptoms within a few weeks after injury, about 10 to 20 percent suffer from persistent PCS (PPCS) that can continue for months and even years after the injury . The etiology of PPCS has been controversial for many years, with different views proposing distinct mechanisms underlying the syndrome. As a result, the major problem is how to predict whether a closed head injury will result in permanent psychiatric sequela. If this will be proved to be possible, then prevention measures, rehabilitation and treatment options could be instituted in the early stages of the process. The Current Study Goals: first, to test the hypothesis of previous studies that psycho-social difficulties which were present before the injury predicts higher level of PPCS. Second, to investigate the psychological mechanisms which mediate the psycho-social risk factors influence the prognostication of PCS. Methods: The children and their parents will be evaluated in four time points: Baseline (within 2 weeks after trauma), 3 weeks, 4, and 9 months post-injury. The Baseline assessment will include pre-injury child and family status, pre-trauma signs of psychological, learning and behavior difficulties. The follow up assessments will include neuro-cognitive evaluation, persistent emotional, physical, cognitive, and behavioral difficulties. Feature directions: To evaluate such as DTI, and MEG as predictors of PPCS and their interaction with social and emotional factors. We hope that this will enable identification of vulnerable children earlier on and thus enable timely intervention.
1Ben-Gurion University of the Negev, Faculty of Health Sciences, Beer-Sheva, Israel.; 2Ministry of Health, Anxiety and Stress Research Unit, Beer-Sheva, Israel.; 3Department of Mechanical Engineering Ben-Gurion University, Israel;
Background: While PTSD and mTBI are both well-described in the general population, the literature concerning PTSD and/or mTBI in the elderly is scant. Age at injury is likely to influence the way the brain can respond and repair itself as a result of an injury. The objective of this study was to explore the question of how age at the time of blast exposure affects behavioural and cognitive responses. Methods: Non-anesthetized middle-aged rats (13-14 m) and young rats (3-4 m) were exposed to an explosive blast-wave. Validated cognitive and behavioral paradigms were used to assess both PTSD-phenotype and mTBI-phenotype. Neurons from hippocampus and amygdala were reconstructed and evaluated. BDNF and NPY were also evaluated. Results: Naïve middle-aged rats displayed very heterogeneous individual responses. Whereas some middle-aged rats performed as well as young rats, others showed pronounced cognitive deficits, several being unable to find the platform at all. The variance made it complicated to set "normal" criteria for learning patterns. Age-related impairments in hippocampus-dependent spatial learning and memory were not associated with a loss of neurons and may be related to synaptic plasticity changes. Despite this, the middle-aged rats displayed overall significantly worse behavioral outcomes following blast exposure compared to young rats. This finding was especially evident for depressive–related behaviour, which was not observed at all in younger rats. These results indicate that middle-aged rats respond to blast exposure differently than young rats and that age is an important factor to consider in pre-clinical efficacy studies. Conclusions: The study emphasises the complexity of working with older subjects, both in terms of determining "baseline norms" and in terms of the pattern of responses to the paradigm. These characteristics are also found in regard to studies involving older human subjects, certainly in terms of age-related baseline characteristics
1Department of Anxiety and Stress Research Unit, Beer-Sheva Mental Health Center; 2Ministry of Health and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; 3Department of Mechanical Engineering Ben-Gurion University of the Negev, Beer Sheva, Israel. ;
While posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are both well-described in the general population, the literature concerning PTSD and/or mTBI in the elderly is scanty and patchy. There are indications that both PTSD and mTBI in old age presents unique features. The brain undergoes a series of structural and functional changes during the aging process. Along with anatomical and functional declines, the cerebral levels of neurotransmitters, neurotrophic factors and nerve growth factor are dramatically reduced in aging brains. Therefore, age at injury is likely to influence the way the brain is able to respond and repair itself as a result of developmental status, extent of anatomical, morphological and cellular senescence. The overall objective of this study was to explore the question of how age at the time of blast exposure (age at injury) affects behavioral and cognitive responses in multiple neurological, behavioral, molecular, morphological and imaging domains over an extended time course. We employed a controlled experimental blast-wave paradigm in which non-anesthetized middle aged male rats (12-13 month) were exposed to visual, auditory, olfactory, and tactile effects of an explosive blast-wave produced by exploding a thin copper wire. Validated cognitive-behavioral paradigms were used to assess both mTBI-, PTSD- and depressive-phenotypes on days 7–14 following the blast. The results demonstrate a degree of heterogeneity in individual responses to the experimental blast-wave, which was different than the patterns of younger animals. At old age, exposure to the experimental blast wave did elicit mTBI-like phenotype, PTSD-like phenotype and combined mTBI-PTSD-like symptoms and also elicit a high percentage of depressive–like phenotype, which not observed in younger rats. A better understanding of the mechanisms of age-related compromise may inform the development of therapeutic interventions to mitigate age-related risk.
1Department of Anxiety and Stress Research Unit, Beer-Sheva Mental Health Center, Ministry of Health, Beer-Sheva, Israel; 2Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; 3Department of Mechanical Engineering Ben-Gurion University of the Negev, Beer Sheva, Israel;
Background: In a previous study, we employed a controlled experimental blast-wave paradigm in which rats were exposed to explosive blast-wave produced by exploding a thin copper wire. We found a degree of heterogeneity in individual responses to this exposure: Whereas most exposed animals did not demonstrate any behavioral or cognitive abnormalities, in a number of rats exposure did elicit either a PTSD-like phenotype or mTBI-like behavior, or combined mTBI-PTSD-like symptoms. Since dysregulation of the HPA axis is thought to underlie trauma-related (psycho-)pathology, we first evaluated the endogenous serum corticosterone levels at different intervals after blast exposure. Subsequently, the efficacy of various doses of exogenous hydrocortisone therapy given immediately after blast-exposure was evaluated. Methods: Non-anesthetized rats were exposed to low pressure blast-wave. Blood was obtained from the rats by sublingual puncture under Isoflurane-anesthetized. Simultaneously, combining of cognitive and behavioral paradigms were used in order to determine the rats' performance. We subsequently evaluated the behavioral and cognitive effects of various doses of exogenous hydrocortisone to non-anesthetized exposed rats 1 hour after exposure. Results: Retrospective analysis revealed that the PTSD-phenotype group exhibited a significantly blunted corticosterone response to blast exposure compared to all other groups. We found that 125 mg/kg hydrocortisone given 1h post blast exposure was effective in reducing the prevalence of PTSD-phenotype. No difference in prevalence of the mTBI-phenotype was noted. Conclusions: Faults in the generation of an adequate and timely endogenous corticosteroid response of the HPA-axis unfavorably alters the trajectory of trauma exposure. Corticosteroid treatment is a feasible avenue for clinical interventions for attenuating PTSD. Our results suggest that mTBI and PTSD may have distinct biological and clinical profiles.
1University of Haifa;
Although not currently classified among the core symptoms of attention-deficit/hyperactivity disorder (ADHD), abnormal emotion has been long recognized as a characteristic of ADHD. Although the majority of the research on ADHD has focused on executive functions, accumulating evidence suggests emotional deficits, including deficiencies in emotion regulation and recognition of facial emotional expressions. In this talk, I will present two studies suggesting maladaptive abnormal orienting of attention towards emotional distracting information among young adults diagnosed with ADHD, compared to matched control participants. These findings will be discussed in the context of possible clinical implications, and general shred neurocognitive systems mediating attentional and emotional functions.
1Psychology department, University of Haifa, Haifa, Israel 3498838;
Objective: To investigate diet and taste responses in immigrant dietary acculturation. Design: In a cross-sectional design we queried diet, and tested taste responses, comparing young new immigrant Ethiopians (EI), veteran Ethiopian immigrant (ES), and native Israelis (NS). Setting: University and immigrant center Participants: EI (~0.5y since immigration, n=20), ES (~13y, n=30), NS (n=82). Results: Across acculturation groups, dietary energy, protein, fat, and sodium increase, whereas carbohydrates, K+ and Ca++ do not differ. Corrected for energy intake, only sodium increases. EI intake less dietary sodium, like foods with less sodium content, salt their food less, yet show a greater hedonic response to salt taste. In contrast, preference for sweet does not differ across groups. Basic-taste psychophysics, PROP (6-n-propylthiouracil) responses, and lingual fungiform papillae density, differ by group (and sex), but do not relate to dietary intake. Conclusions: Beyond energy, increased sodium intake is the prominent dietary change in this immigrant community. Taste psychophysics, lingual fungiform papillae density, and the genetic response to PROP, may also change. Similar alterations in taste responses might obtain in other forms of dietary flux, eg for weight control, or in the taste changes following bariatric surgery. Understanding dietary acculturation can focus efforts (eg on sodium), to anticipate the disease burden of diets of affluence among immigrants. Yet, these immigrant’s nutrition is healthier in its low fat and sodium, suggesting that nutritional advice should focus on preservation, as well as prevention. Our study adds Ethiopian nutritional acculturation to that of the varied immigrant groups around the world.
1Department of Neurobiology - Weizmann Institute of Science;
Social chemosignals are volatiles secreted by one individual to affect behavioral, physiological and hormonal state of other individuals. Growing evidence suggests that chemosignals likely play an important role in human social behavior, mostly without conscious awareness. A hallmark of autism spectrum disorder (ASD) is difficulties in social communication. We hypothesized that a portion of the inability to read social cues in ASD may reflect an inability to read social chemosignals. In a series of experiments we tested autonomic non-verbal physiological and behavioral responses to three different chemosignals in high-functioning adults with ASD and in typically developed (TD) controls. We found that "Fear sweat" (sweat obtained from individuals in a state of fear) drove decreased arousal in TD yet increased arousal in ASD (nTD = 13, nASD = 15, F1,24 = 13.5, p < 0.005, Cohen's d' = 1.5). The putative chemosignal hexadecanal significantly reduced the physiological startle response in TD but not in HF-ASD (nTD = 16, nASD = 16, F1,30 = 7.7, p < 0.01, d'=0.98). Finally, the putative chemosignal androstadienone, a sweat-bound molecule that effects arousal, significantly increased physiological arousal in TD but not in ASD (nTD = 23, nASD = 17, F1,38 = 7.8, p < 0.01, Cohen's d' = 0.93). Taken together, these results suggest altered physiological responses to subliminal social chemosignals in ASD
1Angelman Clinic, Pediatric Neurology Unit, Sheba Medical Center, Tel-Hashomer, Israel.; 2Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel.; 3The Sackler school of medicine, Tel Aviv University, Tel Aviv, Israel.;
Angelman's syndrome is a genetic neurodevelopmental disorder with a frequency of ~1:15,000 live births that is characterized by severe global developmental delay, absence or marked paucity of speech, gait and movement abnormality, epilepsy, hyperactivity and disordered sleep. Over twenty years have passed from the clinical description of Angelman's syndrome in 1965 to the discovery of the deletion on the maternal chromosome 15 in 1987, and additional ten years passed until the discovery of the relevant gene – UBE3A. However, recent years are characterized with multiple discoveries related to unique biochemical pathways and genetic mechanisms in the basis of this syndrome, and bear with them the hope for possible genetic therapy for this syndrome in the near future. In this talk I will briefly go over the clinical phenotype and genetic basis of Angelman's syndrome and then detail some of the major recent discoveries related to biochemical and genetic mechanisms underlying the syndrome and their implementation in current and future planned clinical trials.
1Haifa University ; 2Weizmann Institute;
Previous research has established the importance of interpersonal synchrony in promoting a range of positive social outcomes such as affiliation, cooperation and rapport, emphasizing its role in the formation of effective social interaction. The present study tested the hypothesis that impaired ability to synchronize with other members of the group characterizes individuals with high autistic traits. We used a novel computerized task in which a group of participants were represented as different colored ball shaped figures moving along a computer screen. The level of synchrony of each participant with the group was tested in both (і) free movement (control condition) and (іі) instructed synchrony (experimental condition). Autistic traits severity was measured using AQ questionnaire. We found a significant interaction effect between the type of condition and the level of autistic traits, indicating that individuals with high autistic traits were less synchronized with the group compared to individuals with low autistic traits in the instructed synchrony condition. These results demonstrate the difficulty of individuals with ASD to synchronize with others in the context of group coordination. Moreover, employing a paradigm that measures interactions of individuals within a group provides a highly ecological setting to study social behavior in ASD and may offer novel insights into the mechanisms that underlie the profound behavioral disturbances observed in ASD.
1Educational Neuroimaging Center, Technion, Haifa, Israel; 2Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
Mood and behavioral disorders are separate diagnostic categories within DSM-5. Evidence suggests that children with mood or with behavioral disorders have comorbid reading difficulties. However, these difficulties are concluded as secondary to their primary diagnosis. A question arises as to the differences in reading ability and neural circuits related to reading among children with emotional, behavioral and children with dyslexia using MRI. Functional resting state and DTI data and reading measures were collected in children with mood, behavioral disorders, children with reading difficulties and typical readers. Reading measures were correlated with both functional and structural data. Children with dyslexia demonstrated the most severe reading challenges, followed by children with mood disorders and behavioral disorders. Differences in functional and structural connectivity were related to this reading alteration across groups. Neurobiologically, those results highlight the different neural circuits supporting reading ability in different psychiatric and developmental disorders. More importantly it points at the additional challenges children with psychiatric disorders suffer from in the academic field and provide potential biomarkers differentiating children with dyslexia suffering from emotional challenges from those with emotional disorders suffering from reading difficulties.
1The Pediatric Neurology and Developmental Unit, Loewenstein Rehabilitation Hospital;
Objective: The aim of the present study was to find whether the prevalence of Sensory Processing Disorder (SPD) symptoms is similar among children with attention-deficit/hyperactivity disorder (ADHD) and typical controls, and whether SPD symptoms affect daily function among children with ADHD. Methods: 77 children, aged 8-11 years (37 children with ADHD and 39 typical controls) were recruited. The Conner's Parent Rating Scale–Revised: Short Form (CPRS-R:S) was used to profile ADHD symptoms. The Short Sensory Profile (SSP) was used to measure sensory processing abilities. The Children Activity Scale for Parents (ChAS-P) was used to evaluate children’s difficulties in daily function. Results: The SSP total score of the ADHD group (142.13±25.98) was significantly lower than that of the control group (180.08±11.68; t=-8.23). In the ADHD group, 65.8% of children had an abnormal SSP score indicating SPD, compared to only 2.6% in the control group (χ2=34.40, p<.001). The daily function of children with ADHD was significantly lower than in typical controls (ChAS-p mean 3.95±0.68; and 4.78, ±.36 in the ADHD and control groups, respectively) (t(75)= -6.71, p<.001). The largest differences were found in the category of activities involving executive functions (3.7 ±.79; and 4.76 ±.44). Children with ADHD and abnormal SSP scores, had a significantly lower daily functional ability than controls (p<.001). In contrast, children with ADHD but normal SSP had only marginally lower daily functional abilities than controls (p=.128). Overall, males had lower mean ChAS-P scores than females, however the differences were statistically-significant only among the children with ADHD. An abnormal SSP score was a weightier factor in the ChAS-P performance for males than females. Conclusion: The present study supports the importance of SPD as a possible specifier of ADHD in children that correlates with functional consequences.
1Psychology Department, Ben Gurion University; 2Cognitive and Brain Sciences Department, Ben Gurion University; 3Public Health Department, Ben Gurion University; 4Pre School Psychiatry Unit, Soroka Medical Center; 5Physiology and Cell biology Department, Ben Gurion University;
The Negev Autism Center (www.negevautism.org) is a collaborative effort by researchers at BGU and physicians at Soroka Medical Center who study and treat autism in the Negev. Over the last three years we have created a shared database with a variety of information about over 500 children who were diagnosed with autism in Beer Sheva during this period. A subset of these children participated in prospective polysomnography exams at the Soroka sleep lab. We examined the sleep quality of these children using both parental reports of sleep disturbances as reported by the Children’s Sleep Habits Questionnaire (CSHQ) and standard polysomnography measures. Our results revealed decreased amounts of REM sleep and more shallow sleep (i.e., weaker power in lower frequencies) in autism. Shallower sleep and decreased proportion of REM sleep may indicate that sleep problems in autism are generated by lower sleep pressure/drive. We examined the relationship of these abnormalities to a variety of behavioral measures including autism severity as measure by the ADOS test.
1Department of Psychology, University of Haifa, Haifa, Israel; 2Department of Genetics, Stanford University, Stanford, California, USA; 3Faculty of Education in Technology and Science, Technion, Haifa, Israel; 4Faculty of Civil and Environmental Engineering, Technion, Haifa, Israel; 5Bioinformatics Core Unit, University of Haifa, Haifa, Israel; 6Department of Marine Biology, Leon H. Charney School of Marine Sciences, University of Haifa, Haifa, Israel; 7The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel;
Adenosine to inosine (A-to-I) RNA editing is an epigenetic process that entails site-specific modification in pre-mRNA catalyzed by adenosine deaminases acting on RNA (ADAR). The serotonin receptor 2C (Htr2c), where editing occurs at five sites yielding 32 putative mRNA variants, is one of the best-studied examples of A-to-I RNA editing in coding regions. Recently developed techniques allow the detection of multiple editing sites with high accuracy, but a high-throughput investigation of editing in the rat brain has not been performed. Here, we used microfluidics-based multiplex PCR sequencing (mmPCR-seq) to determine age-, region- and stress-induced changes in editing at 146 pre-selected, conserved sites in the rat prefrontal cortex (PFC) and amygdala (AMY). Since we previously showed that the effects of stress on behavior and gene expression can be transmitted across generations, we asked whether changes in RNA editing patterns and ADAR gene expression could be observed in first- and second-generation offspring of female rats exposed to prereproductive stress (PRS). We found that in line with previous studies, editing was higher in adult (P60) compared to neonatal (P0) rats, and this effect was uncoupled from changes in the expression of ADAR enzymes. At P0, editing levels were lower in PFC compared with AMY. Stress had little effect on global editing levels, but increased editing at the Htr2c A site. Htr2c editing was significantly altered in offspring of female rats exposed to PRS across 2 generations, and differences in Htr2c isoform distribution were more robust in first- and second-generation offspring compared to rats directly exposed to stress. In conclusion, mmPCR-seq can be used to accurately detect developmental and region-specific changes in RNA editing in the rat brain. Our findings point to stress-induced alterations in RNA editing that may explain previously observed transmission of behavior and gene expression patterns across generations. Support: IGS ISF 484/10, HZ BSF Rahamimoff 2015
1School of Behavioral Sciences, Tel Aviv-Yaffo Academic College ; 2Dep. Of Psychology, Ben Gurion University of the Negev; 3Dep. Of Education and Psychology, The Open University;
Introduction: Preterm birth (gestation < 37 weeks), account for 11% of all live births worldwide, represents a major challenge to public health .It is well-established in literature that even under low medical risk conditions, premature birth is associated with short-term and long-term neurodevelopmental impairments in a vast range of domains, including impairment in motor development, cognitive functioning and vulnerability for the development of anxiety disorders. However, the correlational nature of these studies did not enable an experimental exploration of the mechanisms that underlie these associations. To address this gap in the literature, we propose a preterm birth mouse model of anti-progesterone RU486 injection to better understand the link between prematurity and behavioral and biological outcomes in the offspring. Method: In lower mammals such as mice, there is a reduction in progesterone levels preceding the parturition process. a s.c. injection of 150 μg of the anti-progesterone RU486 (also known as Mifepristone) into pregnant mice induced parturition of pups within 18 hours. Normally, ICR mice full-term pregnant is 20-21 days, and we managed to induce parturition of living pups early as the age 18 days. We tracked the pup’s weigh along different ages, and tested the pup’s motoric abilities at the age of 5 days using righting reflex test, cognitive functioning (using Morris Water Maze and Y maze) and anxiety-like behaviours (using Elevated Plus Maze) at the ages of 30 days and 60 days. Results: in comparison to full-term born mice, Preterm-born mice weighed significantly less in along different ages, and demonstrated poorer performances at righting reflex test, MWM and EPM. Conclusion: The implication of the preterm birth mouse model of anti-progesterone RU486 injection successfully inducing long-living premature mice, and enable an experimental investigation of the developmental impairments associated with prematurity, as well as better understanding of the biochemical mechanism underlying these impairment. Preliminary data pointing that preterm-born mice tend to demonstrate motoric and cognitive difficulties, as well as vulnerability to anxiety.
1Department of Psychology, Ben-Gurion University of the Negev; 2Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev; 3School of Behavioral Sciences, Tel Aviv-Yaffo Academic College ;
Background: Chronic exposure to the commonly used OP pesticide chlorpyrifos (CPF) had been shown to cause neurodevelopmental deficits both in humans and in rodents. Exposure to pesticides was associated with smaller head circumference, abnormal reflexes and decreased cognitive ability in infants. Those associations were stronger among children of mothers with low paraoxonase-1 activity (PON1). PON1 metabolizes some OP’s, CPF among them. The aim of the present study was to assess the interaction between paraoxonase and prenatal exposure to CPF. PON1 null mice are more susceptible to the lethal effects of several OP's, but it is not known if the absence of the enzyme affects susceptibility to long-term behavioral effects of CPF. We hypothesized that PON1 knockout mice will be more susceptible to CPF compared to wild type C57BL6/J (B6) mice. Methods: B6 and PON1 null mice were treated with 0.5 mg/kg of CPF or with vehicle on gestational days 12-15. On postnatal days (PND’s) 5-12 early neurodevelopmental motor abilities were assessed by measuring 3 neonatal reflexes. In adulthood, PND 90, social behavior was evaluated using the social preference (SP) and social conditioned place preference (SCPP) tasks. In addition, on PND 90 the ability to establish a non-social conditioned place preference was assessed in the food conditioned place preference task. Results: Prenatal exposure to 0.5 mg/kg of CPF caused delayed development of neonatal reflexes in PON1 mice, but not in B6 mice. In adulthood, PON1-/- mice showed reduced sociability in the SP task, and decreased SCPP regardless of whether they were exposed to CPF. In B6 male mice, CPF resulted in reduced SCPP compared to B6 that were not exposed. Conclusion: Our data indicate that in even a very low dose of prenatal CPF can have adverse effect on higher order social behaviors. In addition, we found developmental and social deficits in PON1 KO mice that have not been reported previously.
1The Hebrew University of Jerusalem, Israel;
ADHD is assumed to be associated with increased engagement in risk-taking behaviors such as dangerous driving, substance abuse, gambling and more. In order to better comprehend what underlies this association we took a behavioral economics approach, which distinguishes between subjective perceptions of risk and benefit and the seeking or aversion attitudes toward the perceived risk and benefit. Previously we showed that higher level of ADHD symptoms in the general population was linked to higher level of engagement in risk-taking behavior and of benefit perception, but not with level of risk perception or risk attitude. To further these findings, we developed a new questionnaire that was based on the risk outcome, and used a case-control study design controlling for various demographic and clinical variables. It was shown that compared to controls and beyond background characteristics, adults with ADHD demonstrated increased risk-taking behavior across outcome domains and increased benefit perceptions, but similar risk perception and attitude towards risk. These findings demonstrate that use of behavioral economic paradigm leads to meaningful conclusions in studying risk-taking behavior by people with ADHD.
1Sagol Dept. of Neurobiology, Faculty of Natural Sciences, Univ. of Haifa;
Obesity is considered a critical factor in the prevalence and development of mental disorders and it is becoming one of the most serious public health challenges of the 21st century. Juvenility is a critical development stage characterized by major hippocampus changes and vulnerability to food. We recently demonstrated that long-term exposure for 3 months to high fat diet (HFD) starting from juvenility to adulthood induced enhancement of amygdala function and impairment of hippocampal function. Interestingly, the same exposure to HFD but at adulthood and for 3 months did not result in changes in hippocampal or amygdala-dependent functions (Boitard et al. 2014). Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis was reported to mediate these effects. Here, we focused on the effects of short- term exposure to HFD in the juvenile or adult animals on changes in long-term potentiation (LTP) in the Schaffer collateral-CA1 pathway (hippocampus), spatial memory (hippocampal dependent memory). Further, we examined the dependency of these effects on glucocorticoid receptors (GRs). Exposure to short-term HFD resulted in enhanced CA1-LTP in adult animals and impaired LTP in juvenile animals CA1. After application of GRs antagonist (RU486) effects of HFD no longer observed; the antagonist abolished the induction of LTP in the adult animals while in the PW it enhanced the induction. In accordance with the electrophysiology results, short-term exposure to HFD enhanced spatial memory in adult rats and disturbed it in juvenile animals. Our results show qualitatively different mechanisms that control the modulatory effects of short term HFD on spatial memory and CA1 plasticity in the two age groups. Additionally, GRs may have an important role in modulating plasticity. These differences in the effects of HFD between young and adult brains may explain the increase in emotional and behavioral disorders in children.
1Ariel University, Department of Molecular Biology , Ariel, Israel;
While glucocorticoids are essential to fetal development and nutrient transfer via the placenta, excessive maternal glucocorticoids may cause maladaptive programming of the Hypothalamus Pituitary Adrenal (HPA) axis in utero, which is implicated in anxiety disorders in adulthood. Among two selectively bred mice strains, Dominant (Dom) or Submissive (Sub) phenotype predicts adaptive or maladaptive HPA axis programming in response to prenatal restraint stress (PNS). In order to test the role of placental glucocorticoid signaling in resistance or sensitivity to PNS, pregnant dams were treated with either DEX (0.1 mg/kg, s.c.) or vehicle one hour prior to PNS on gestational days (GD) 15-17. We assessed alterations in glucocorticoid signaling of Dom and Sub placentas in response to PNS, alongside their ability to cope with acute stress. Placental weight was significantly lower among stressed Sub pregnancies, relative to Dom counterparts, which may be explained by dramatically lowered levels of placental glucocorticoid receptor (GR) among Sub mice exposed to PNS. Furthermore, placental levels of the enzyme 11beta-hydroxysteroid dehydrogenase-2 (HSD2), responsible for deactivation of glucocorticoids, were increased among Dom mice in response to PNS, while Sub placentas showed no change in HSD2 levels. Pre-restraint treatment with DEX rendered an anxiolytic effect upon adult Dom offspring in the Elevated Plus Maze (EPM), as opposed to the expected, anxiogenic effects seen among Sub mice. We conclude that the anxiolytic effects of DEX upon Dom mice born to stressed pregnancies may be mediated by alterations in placental glucocorticoid signaling. Further study of the genomic landscape of Dom mice should reveal biomarkers of resilience to stress.
1Technion, Israel Institute of science; 2Ort Braude College;
Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood primarily characterized by an inappropriate activity levels of impulsivity hyperactivity, and inability to sustain attention. It has recently become evident that Individuals with symptoms of ADHD consistently demonstrate subtle abnormalities on motor examination. In this study we asked: are these characteristics rooted in deficient motor plan preparation, prior to actual execution or are they mainly correlated with online execution? To this end, we compared motor planning mechanisms of ADHD and control subjects based on their effect on later observed kinematic characteristics. We monitored hand movement following planning conditions that differed in available preparation time, and evaluated the differences in the following movement in a control group. We further checked if similar differences in the following movement were found for participants with ADHD. Our findings showed that when there was sufficient planning time, people without ADHD seem to have a motor plan ready, and when presented with a ‘GO’ cue, they immediately initiated a planned movement with a bell shaped velocity profile. When planning time was not sufficient, they started the movement in a delayed time, possibly indicating that they needed to complete a movement plan. However, people with ADHD, even when provided with sufficient preparation time, did not start movement immediately after the ‘GO cue, possibly indicating that even for this planning interval they did not have a motion plan ready. The following movement was not only delayed, but had a velocity profile that was not bell shaped and had several peaks. We further found differences between control and ADHD participants in variability and jitter of movements. Our results suggest that ADHD motion characteristics, are associated with an immature motor plan. Based on the results we propose a paradigm to evaluate deficiencies in motor planning.
1Psychology Department, The Hebrew University of Jerusalem; 2The neuropsychological Unit, Schneider Children’s Medical Center; 3Department of Medical Neurobiology, Hebrew University of Jerusalem; 4Hadassah Hebrew University Braun School of Public Health;
Introduction: The possible contribution of environmental exposures to the growing prevalence of neurodevelopmental disorders such as the autistic spectrum disorder and attention deficit disorder should be studied. Phthalates, which have ubiquitous exposure in the general population, have been suggested as having neurodevelopmental effects. We aimed to study the association of intrauterine exposure to phthalates and neurodevelopment of two years old toddlers. Methods: We conducted a cohort study of pregnant women. First trimester urine was analyzed for phthalate metabolites. Development was assessed at 24 months of age in 83 offspring. Developmental information was collected in interviews and included the Child Behavior Checklist (CBCL), the Preschool Activity Inventory (PSAI), Home Observation Measurement of the Environment (HOME inventory), and Ages and Stages Questionnaire (ASQ-3), as well as, day care settings, diet, and sleeping habits. Results: Intrauterine phthalate levels were associated with CBCL scores, indicating that the higher the phthalate levels, the worse the children did in terms of internalizing behavior problems. Similarly, phthalates negatively correlated with the ASQ communication score, indicating that higher metabolite levels were associated with worse ASQ scores. No associations were found for the PSAI and HOME scores and metabolite levels. Conclusion: Phthalates may be associated with internalizing behavior and communication in young children. Increasing the sample may allow drawing more meaningful conclusions. Future analyses will extend follow up to 42 months.
1Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel; 2The Autism Center, Department of Pediatrics, Assaf Harofeh Medical Center, Zerifin, Israel;
Internal action models are brain templates for sensory-motor coordination that are suggested to be impaired in Autism spectrum disorder (ASD). However, whether and how impaired internal action models relate to the major phenotype of ASD, namely impaired social communication, remains unclear. Olfaction relies on an internal action model known as the sniff-response, whereby nasal airflow parameters are rapidly modulated in accordance with odorant content. For example, pleasant odors are automatically sampled with strong sniffs, yet unpleasant odors are sampled with weak sniffs. Thus, by measuring nasal airflow (sniffs) alone we obtain a non-verbal measure of olfactory perception and processing. To test the hypothesis that the sniff response is altered in ASD, we delivered pleasant and unpleasant odors while simultaneously precisely measuring nasal airflow in 36 children; 18 with ASD and 18 age and gender matched typically developing (TD) controls. TD children generated a typical adult-like sniff-response, modulating airflow in a valence-dependent manner within 305 milliseconds of odor onset. In contrast, ASD children had a profoundly altered sniff-response, sniffing equally regardless of odor valance. At the single subject level this difference allowed for 81% correct ASD classification based on the sniff-response alone (binomial, p < 0.001). Moreover, the sniff-response was correlated with ASD severity such that increasingly aberrant sniffing was associated with increasingly severe ASD (r = 0.75, p < 0.001). Tellingly, aberrant sniffing was associated with the generalized social (r = 0.72, p < 0.001) but not motor (r = 0.12, p = 0.68) impairment in ASD. These results uncover a novel language-free task-free ASD marker that implies a mechanistic link between the underpinnings of olfaction and ASD. This supports the impaired internal action model of ASD and links it to impaired social communication.
1School of Psychological Sciences, Tel Aviv University; 2Department of Psychology, Arizona State University ;
Introduction: The infant cry is a strong stimulus “programmed” to elicit parental response. Research has suggested that parental reactivity to crying is a personal characteristic that is likely to influence parents’ responses to their infant and thus influence early development. In a previous cross-sectional study we found that parents of infants with sleep problems are more reactive to crying compared to parents of infant without sleep problems (Sadeh et al., 2016). The present study aims to assess the validity of the PCR construct in a longitudinal study and to assess the associations between this parental characteristic and infant sleep. Methods: This is a longitudinal study in progress, with four assessment points (pregnancy, 3, 6 and 12 months). Until now, 115 couples expecting their first child have been recruited, 30 of which have completed the12-month assessment. Assessments of PCR include responses to video (the IDICV paradigm) and audio recordings (the RICAS paradigm) of crying infants (Sadeh et al., 2016). In the IDICV participants are asked to indicate the point in time when they feel it is essential to intervene and soothe a crying infant. The delay time is used as a measure of cry tolerance. Infant sleep is assessed using actigraphy, sleep logs and parent reports. Results: PCR appears to be a stable individual characteristic with correlations ranging between .45 and.66 for repeated administration of the IDICV across pregnancy, 3 months and 6 months in mothers and fathers (F=10.4, p< .005). In addition, fathers are consistently more tolerant to infant crying than mothers. Preliminary findings demonstrate curvilinear links between PCR and sleep, indicating that both extremes of very low and very high PCR at pregnancy are associated with poorer actigraphic sleep quality at 3 months. Discussion: PCR may play a role in parental behaviors related to infant sleep, such as excessive or insufficient involvement in soothing infants at bedtime, which may contribute to the development of poorer sleep quality.
1Technion - Israel Institute of Technology; 2Beer Yaakov Mental Health Center;
In our previous research on ADHD, we have found that methylphenidate affects sustained attention and working memory performance of adults with and without ADHD in a similar deree, while no effect was registered in decision making tasks (Agay, Yechiam, Carmel, & Levkovitch, 2010; 2014). Our new research examines whether similar effects can be observed for Hypericum perforatum (H. perforatum) which increases synaptic plasticity and monoamines (noradrenaline, dopamine, and 5-HT) levels while having an inhibitory effect on the binding of GABA ligands. Study 1 is a meta-analysis of 13 preclinical experiments. It shows a strong positive effect on spatial memory performance for healthy intact rodents. Study 2 is an initial investigation of healthy human adults. Participants underwent two sessions: one in which they received hypericum and another with placebo (double blind, random order). Two dosages of hypericum were used: 250 mg and 500 mg of the herbal extract (Remotiv 250 and 500) containing 0.5 mg and 1 mg hypericin, respectively. About 1.5 hours following drug administration, participants performed several short term and working memory tasks including the forward and backwards Digit Span tasks, Operation Span, and Symmetry Span as well as the Test of variables of attention and the Groton maze learning task which assesses spatial memory. Pilot findings indicate that in the three verbal memory tasks there was generally a positive effect of the 250 mg dosage and a negative effect for the 500 mg dosage. Both dosages also reduced negative affect on the Positive And Negative Affect schedule and trait anxiety on the State Trait Anxiety Inventory compared to a pre-task baseline. Taken together these studies suggest that H. perforatum and methylphenidate reduce the gap between individuals with poor working memory and their counter-parts. For methylphenidate this effect emerges with no ADHD diagnosis; and for H. perforatum with no anxiety and depression disorder.
1Sagol School of Neuroscience, Tel Aviv University, Tel Aviv.; 2The Behavioral Neurogenetics Center, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer.;
Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous microdeletion of about 26 genes from chromosomal region 7q11.23, characterized by hypersociability and unique neurocognitive abnormalities. Of the deleted genes, general transcription factor II-i (GTF2I) has been linked to hypersociability in WS, though the molecular and cellular mechanisms affected by GTF2I deletion are poorly understood. To dissect the neural function of Gtf2i and its relevance to WS, we previously deleted Gtf2i selectively in neurons and found WS-relevant abnormalities, including neuroanatomical defects, fine motor deficits, increased sociability and anxiety. Unexpectedly, we found in the mutant mouse deficits in myelination properties on the molecular, cellular, structural and physiological levels. Normalization of the impaired axonal conductivity in the mutant mice rescued behavioral deficits selectively. Importantly, transcriptome analysis of human frontal cortex from WS patients similarly revealed myelination-related deficits. To further characterize the myelination deficits in WS patients, our next step will be measuring their neuronal conductivity utilizing the Visual Evoked Potentials (VEP) test. Ultimately, we plan to treat WS patients with a drug that will increase axonal conductivity and test its effects on fine motor skills, cognitive capabilities and social behavior.
1The School of Psychological Sciences and The Sagol School of Neuroscience;
Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous microdeletion of about 26 genes from chromosomal region 7q11.23, characterized by hypersociability and unique neurocognitive abnormalities. Of the deleted genes, general transcription factor II-i (GTF2I) has been linked to hypersociability in WS, though the molecular and cellular mechanisms affected by GTF2I deletion are poorly understood. To dissect the neural function of Gtf2i and its relevance to WS, we selectively deleted Gtf2i in forebrain excitatory neurons and found WS-relevant abnormalities, including neuroanatomical defects, fine motor deficits, increased sociability and anxiety. Unexpectedly, we found that in the mutant mouse cortex 70% of the genes with significantly decreased mRNA level were involved in myelination. Furthermore, we found reduced mature oligodendrocyte cell numbers, reduced myelin thickness and impaired axonal conductivity. Normalization of impaired axonal conductivity rescued behavioral deficits selectively. Importantly, transcriptome analysis of human frontal cortex from WS patients similarly revealed significantly lower mRNA level of myelination-related genes, along with reduced myelin thickness and decreased mature oligodendrocyte cell numbers. Our study provides the first molecular and cellular evidence for myelination deficits in WS linked to the deletion of Gtf2i in neurons. Together these data suggest new paths to explore the neurobiological etiology of WS and potential therapeutic targets for associated social and cognitive abnormalities.
1Department of Psychology, University of Haifa, Haifa, Israel;
We have previously shown that pre-reproductive stress (PRS) to adolescent female rats alters anxiogenic behavior in their first- and second-generation offspring in a sex-dependent manner. PRS also changed corticotropin releasing factor 1 (CRF1) mRNA expression in the frontal cortex and oocytes of the exposed females and in their offspring’s brain at birth. Here, we tested whether maternal treatment with the CRF1 antagonist NBI 27914 (NBI, 5 mg/ml; 5 days) or the antidepressant drug fluoxetine (FLX, 5 mg/kg, 7 days) would reverse the behavioral and CRF1 expression abnormalities induced by PRS. Adolescent female rats (F0) were exposed to a 7-day stress procedure, and were treated subchronically with NBI or FLX prior to mating. Female rats (F0) and their offspring (F1) were weighed regularly, and behavior in dams and offspring was assessed on P60. Brain samples were collected from offspring at birth to examine CRF1 mRNA gene expression. In F0, PRS increased pre-pregnancy weight gain and decreased locomotion in the open field (OF). Both male and female offspring of PRS dams showed abnormalities in the open field (OF), elevated plus maze (EPM), and fear conditioning (FC) paradigms. Maternal drug treatment reversed these abnormalities in female, but not male, offspring. As previously observed, PRS increased CRF1 mRNA in offspring amygdala at birth, and this effect was reversed by maternal NBI treatment but potentiated by FLX. Interestingly, maternal drug treatment alone also affected offspring weight and behavior. These findings suggest that some of the behavioral and HPA axis-related transgenerational effects of pre-gestational trauma may be altered by post-stress drug treatment, and that different mechanisms may mediate the inheritance of stress to male and female offspring. Support: Israel Science Foundation (484/10).
1Geha Mental Health Center, Petah-Tikva, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Felsenstein Medical Research Center, Rabin Medical Center Campus, Petah-Tikva, Israel; 4Child Neurology, Meir Medical Center, Kfar Saba, Israel;
Objectives: Alteration in peripheral iron indices has been reported in a number of movement disorders, particularly Parkinson’s disease. We hypothesized that iron stores may be diminished in children at an early stage of tic disorder. Methods: Using data retrieved from electronic medical records, A total of 1230 files of child neurology outpatients clinic patients were screened, we compared serum ferritin levels, an indicator of body iron store balance, in drug-naive children diagnosed for the ﬁrst time with tic disorder (study group; N=47, 32 boys/15 girls, aged 8.66–3.17 years) compared to age- and sex-matched children with headaches (comparison group, n=100, 62 boys/38 girls, aged 9.51–3.15 years) treated in the same pediatric neurological clinic. Results: Mean serum ferritin levels were signiﬁcantly lower (-32%, p=0.01) in the tic disorder group compared to the headache group. No signiﬁcant differences were detected in circulatory hemoglobin, iron, transferrin, and platelet count between the two groups. Conclusion: Our ﬁndings suggest that body iron stores may be reduced in children with recent-onset tic disorder.
1The Pediatric Neurology and Developmental Unit, Loewenstein Rehabilitation Hospital, Raanana, Israel ; 2Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel ; 3The child development center of Clalit health services, Natanya, Israel ;
Objective Sleep disorders have been reported in up to 85% of children with ADHD. 40%-60% of children with ADHD exhibit sensory modulation difficulties (SMD) in addition to the core symptoms of ADHD. Children with ADHD who exhibit sensory symptoms have been reported to experience more significant functional difficulties. We aimed to evaluate whether SMD affect sleep characteristics of children with ADHD. Method: 41 children with ADHD and 39 controls (ages 8-11) were recruited and assessed, using the Conner's Parent Rating Scale–Revised: Short Form, the Short Sensory Profile (SSP) and The Children’s Sleep Habits Questionnaire (CSHQ). Results: In the ADHD group, 78.1% of children lower quality of sleep, compared to 21.9% of children in the control group (χ2=16.84, p<0.001). A multivariable model revealed that children with ADHD and SMD had sleep scores that were lower than controls, whereas children with ADHD and no SMD were indistinguishable from controls. Use of stimulants, gender, mother’s education and age had no significant contribution. Conclusion: In this pilot study, we found that difficulties in modulation of sensory input may correlate with lower quality of sleep in children diagnosed with ADHD.
1Sagol Dept. of Neurobiology, Faculty of Natural Sciences, Univ. of Haifa;
Recent studies have shown that consuming Western diet that contains high levels of saturated fats can affect learning and memory processes. Juvenility is a period of continuous brain development marked by structural changes and thus is very susceptible to metabolic challenges. We have recently reported that exposure to high-fat diet (HFD) for 3 months starting at juvenility induced enhancement of amygdala function and impairment of hippocampal function. Interestingly, the same exposure to HFD at adulthood and for the same duration did not result in changes in hippocampal or amygdala-dependent functions (Boitard et al. 2015a). In the present study we aimed to address the question whether HFD-induced cognitive and emotional alterations can be achieved by shorter periods of exposure, considering that during juvenility the brain structures that mediate emotional and cognitive processes are undergoing maturation. We thus focused on addressing the impact of short exposure (7-10 days) in juvenile or adult animals on social recognition memory. Furthermore, as oxytocin is one of the most important neuromodulator of social memory we thus investigated its role in mediating HFD-induced effects on social memory. Our results indicate that short-term exposure to HFD impaired social recognition memory in juvenile animals but not in adult animals. Systemic Oxytocin injection impaired the social memory in rats that were fed control diet and reversed the impairment in memory of social recognition in animals that were on HFD. This is the first study to show that acute exposure to HFD in juvenile animals is associated with impairments in social recognition memory and thus show that exposure to western diet at early age can have adverse effects on social memory.
1Haifa University; 2Ariel University; 3Weizmann Institute of Science;
Joint synchronized actions such as playing, dancing, conversing and even walking together along the street are merely simple examples of how interpersonal synchrony comprise a great deal of our everyday lives. Previous studies have established the importance of synchrony in promoting a range of positive social outcomes such as affiliation, cooperation and rapport, emphasizing its role in the formation of effective social interaction. The present study tested the hypothesis that impaired ability to synchronize with other members of the group characterizes individuals with high autistic traits. We used a novel computerized task in which groups of four participants, represented as colored circles, were instructed to either і) move freely [free movement condition (FM)] or (іі) move in synchrony [instructed synchrony condition (IS)]. Additionally, in a separate experiment we measured the brain activity of two interacting partners simultaneously, using fNIRS. We found a significant interaction effect between the type of condition and the level of autistic traits, indicating that individuals with high, compared to low autistic traits, were less synchronized with the group, in the IS condition. Critically, preliminary analysis of the fNIRS data show interbrain synchrony in the inferior frontal gyrus (a region associated with mimicry) during IS. These results may offer novel insights into the mechanisms that underlie the profound behavioral and neural disturbances observed in autism.
1The Emotion-Cognition Research Center, Shalvata Mental Health Care Center, Hod-Hasharon; 2Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel, Israel; 3The Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University Ramat Gan, Israel; 4Department of Psychology, University of Haifa, Haifa, Israel;
Background: Anxiety disorders are highly comorbid with Attention Deficit hyperactive Disorder (ADHD), and there is a complex interplay between attention and anxiety as a dimension. Both are effected by stimulant medications. While some clinicians base their practice on the fear that stimulants will aggravate anxiety in ADHD patients, recent studies support the opposite. The aim of the current study was to examine if the effects of stimulants on anxiety are specific to ADHD patients, and to have a better understanding of the underlining brain circuits. Methods: This double blind cross over study was conducted on 20 adults with ADHD and 20 adult of a Control group. Anxiety and attention were evaluated repeatedly with questionnaires. Brain activity was recorded with the Magnetoencephalography (MEG) both while performing a cognitive task (2N BACK) and at three rest point expected to present differences in state anxiety: before, after a test trial, and at the end of the evaluation. This was performed on two separate appointments: After receiving 20 mg of methylphenidate on one occasion and after placebo on the other. Results: in adults with ADHD and low state anxiety, the level of anxiety increased after receiving methylphenidate. Subjects in the control group showed no elevation in anxiety following methylphenidate. In terms of MEG readings: High gamma band waves were different in the ADHD and control group and had a positive correlation with cognitive performance in both. In subjects with a high level of trait anxiety the theta/betha ratio rose after the admission of methylphenidate. Discussion: This double blind study showed correlation between admission of methylphenidate and elevated level of state and trait Anxiety, and between the Anxiety level and brain activity. It brings to light questions about the place of Anxiety as a dimension whose importance needs to be appreciated in the understanding and treatment of ADHD.
1Department of Psychology, University of Haifa, Haifa, Israel;
Pre-reproductive stress (PRS) to adolescent female rats alters anxiogenic behavior in first- and second-generation offspring in a sex-dependent manner. PRS also leads to corticotropin releasing factor receptor 1 type 1 (CRF1) gene expression changes in oocytes of exposed females and in offspring brain at birth and in adulthood. Objectives: Here, we asked whether PRS alters the expression of stress-associated microRNAs, which regulate gene expression. We further inquired whether maternal behavior is altered in PRS-exposed rats Methods: Adolescent female rats (F0) were exposed to a 7-day stress procedure, and were mated two weeks later. Oocytes were extracted from a subset of PRS and control rats for examination of miR-34a, miR- 34c and miR-382. Remaining female rats (F0) and their offspring were weighed regularly and examined for changes in dam-pup interaction and aggressive behavior for 12 days following parturition. Locomotor activity and anxiogenic behavior was assessed in dams and offspring on P60. Results: PRS increased pre-pregnancy weight gain and decreased locomotion of exposed females in the open field. The expression of miR-34a and miR-34c decreased, whereas miR-382 expression in oocytes remained unchanged. Maternal self-care decreased in PRS-exposed females, whereas pup care (particularly licking and grooming) increased. Both male and female offspring of PRS dams showed abnormalities in the open field, elevated plus maze, and fear conditioning paradigms. Our findings point to CRF1 as a key player in mediating the transgenerational effects of adolescent stress, and suggest a role for both germline microRNA and maternal behavior as possible propagators of maternal adversity effects.
1BBB-Group, The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel; 2Gonda Brain Research Center, Bar Ilan University, Ramat-Gan, Israel; 3The Advanced Technology Center, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel; 4The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel; 5Pharmacology Division, The Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Israel; 6Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; 7The Interdisciplinary Center, Herzliya, Israel; 8Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 9Department of Psychology, Bar Ilan University, Ramat-Gan, Israel;
Background: Type 2 diabetes (T2D) is associated with increased risk for Alzheimer's disease (AD). There is evidence for impaired blood brain barrier (BBB) in both diseases but its role in the interplay between them is not clear. Here, we investigated the effects of high fat diet (HFD), a model for T2D, on the Tg2576 mouse model of AD in regards to BBB function. Results: We showed that HFD mice had higher weight and more insulin resistance, primarily in Tg2576 mice. HFD also induced hypoactivity in Tg2576 mice and anxiety-like behavior. HFD improved learning of Tg2576 mice tested in a Morris Water Maze in comparison to Tg2576 mice fed with regular diet. MRI scans were performed on all mice at 4, 8 and 12 months of age. Tg2576 mice demonstrated BBB disruption at 8 and 12 months which was reflected in increased gadolinium (Gd) extravasation to the brain. Increased volume of the lateral ventricles was also observed in these mice. However, HFD decreased Gd's extravasation to the brain decreased ventricular volume, thus prevented brain AD common pathology. HFD had no effect on amyloid beta level in the cortex. HFD increased serum HDL-cholesterol levels in both Tg2576 and WT mice and also increased the transcription level of insulin receptor in the hippocampus. Conclusions: Our results suggest that HFD promotes better cognitive function through improvement of BBB disruption and of brain atrophy but not of amyloid beta levels. Cholesterol metabolism and insulin signaling may underlie this protection.
1Department of Neuroscience, Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa 31096,Israel; 2Cognitive Neurology Unit, Rambam Health Care Campus, Haifa, Israel; 3Institute of Human Genetics, Western Galilee Hospital, Naharia, Israel;
Detecting subtle alterations among genetically at risk populations for developing Alzheimer's Disease (AD), in presymptomatic stages will open a time window for intervention and prevention. It is now acknowledged that in order to arrest or reverse the disease progression, compounds will need to be administered much earlier, years prior to the emergence of clinical symptoms of AD. Yet, limited data exist on the presymptomatic stage of AD. The main goal of the current study is to characterize cognitive and neural alterations among healthy participants with near certainty to develop Alzheimer's disease. To that end, in a group of participants with APP duplication (a genetic predisposition for early onset Alzheimer's disease), we aim to characterize the relation between this genetic predisposition, cognitive function, brain structure and functional connectivity. Fifteen APP carriers, in presymptomatic stages, and 15 age-matched controls from the same family were recruited for this study. Participants underwent a 45-minute-long MRI scanning followed by an hour and a half of neurocognitive assessment, psychological screening and neurological examination. Preliminary behavioral results from a task assessing visual short-term memory for objects' identity and location, provide evidence for impaired performance in general item localization precision and in association generation between objects and their locations among carriers. Structural imaging data suggests a trend for reduced hippocampal volume. These results suggest that the unique cohort of individuals may allow to more finely estimate the changes that occur in presymptomatic AD, and perhaps allow to identify potential markers of the presymptomatic stage in non-familial forms of AD.
1Medical Director at Princeton Medical Institute; 2 Senior Attending Physician at University Medical Center of Princeton at Plainsboro; 3Princeton University ;
Alzheimer’s disease is one of the most common precursors to dementia and affects over 5 million Americans to date. Additionally, this disease is associated with people between the ages of 70-90 years old. Although we potentially know the causes of this deleterious disease, there is much to learn about developing new treatments and diagnostic tests to potentially find a cure. Current research suggests immunotherapy is a hopeful potential treatment in preventing the formation of the mutated amyloid proteins. Amyloid is involved with neuronal support and function; once this protein is mutated disastrous effects on the neurons are observed (such as neuronal death). The key to treating and managing Alzheimer’s disease is to identify the disease as early as possible, and develop new pharmaceuticals and other treatment to combat the disease’s progression. This poster presentation is designed to help inform the general public about Alzheimer’s disease, primarily its effects, causes, and potential treatment. Additionally, this poster will also help facilitate urging the public, if they are able to do so, to become involved with the clinical research behind the new developments in treating and finding more information about Alzheimer’s disease.
1Department of Molecular Biology, Ariel University, Ariel, Israel;
Memory disorders are the central contributors to ageing-related cognitive impairments, which are linked to different patterns of sensitivity to stress. Therefore understanding the influence of stress on mechanisms underlying early manifestation of age-related cognitive impairments is of crucial importance. Utilizing social behavior paradigm, we developed animals with strong dominant and submissive behavior exhibiting resilience or sensitivity to stress, respectively. Based on our findings and current knowledge, we hypothesize that inherent sensitivity to stress elicits molecular events, which may be linked to the accelerated aging processes. In this study, we assessed the lifespan of animals with different adaptability to stress. The cohort of mice included 10 males in each of the 3 strains studied (Wild Type (WT), Dominant (Dom) and Submissive (Sub)). We demonstrated that the lifespan markedly differed between Sub and Dom as well as between Dom and WT groups, while no significant difference between Sub and WT groups was observed. These data indicate stress resilient animals have longer lifespan than stress sensitive counterparts, supporting the evidence that stress is a risk factor in developing early onset of aging as well as age-related cognitive impairments, observed in stress sensitive mice. This present study provide a life expectancy survey analysis in our unique mouse model of resilience and sensitivity to stress that will be useful for understanding the pathophysiology events underlying the ageing process.
1Psychology & Behavioral Science Department, Ariel University, Israel; 2Psychology Department, Bar-Ilan University, Israel; 3Psychology Department and Leslie & Gonda Brain Research Center, Bar-Ilan University, Israel; 4Department of Neurology, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel; 5;
Introduction: Anxiety, depression and subjective memory complaints (SMC) are major risk factors for Mild Cognitive Impairment (MCI) and dementia. However, the association between anxiety, SMC and memory clinic help seeking is not clear. In the current study, we assessed state vs. trait anxiety among two groups of people with memory complain: those who seek help in memory clinics (HS) and those who do not (NHS). Methods: HS were recruited from 'Memory Clinic' of Rabin Medical Center, and NHS were recruited from the community. All participants completed memory tests, subjective memory questionnaire, depression questionnaire and state - trait anxiety questionnaire. state anxiety was assessed immediately following memory testing (indicating anxiety triggered by the memory test). Results: Although results in objective memory tests and trait-anxiety showed no differences between groups, the HS reported significantly higher levels of state anxiety, depression and had more SMC compared to the NHS. conclusions: HS with SMC (even those who do not meet any criteria for memory decline) are characterized with risk factors for MCI and dementia. Therefore, HS with SMC should be treated as a high-risk group, even if they do not show objective memory deficits. *Corresponding author: E-mail address: firstname.lastname@example.org
1Tel Aviv University School of Medicine; 2The Academic College of Tel Aviv-Jaffa; 3The Open University;
We have previously shown that an ultra-low dose of THC (delta-9 tetrahydrocannabinol) protected the mice brain from a variety of insults (Ref. 1, 2, 3). A single injection of 0.002 mg/kg of THC (3-4 orders of magnitudes lower than doses that induce the conventional cannabinoid effects in mice) prevented the cognitive damage that was induced by either hypoxia, deep anesthesia, MDMA-toxicity, epileptic seizures or neuroinflammation. THC was applied either 1-7 days before or 1-7 days after the insult, thus providing a wide therapeutic time-window. The protective effect of the single injection of ultra-low THC lasted for at least 7 weeks. The protective effect of THC was accompanied by a long-lasting elevation in pERK, pCREB and BDNF in the hippocampus and frontal cortex of the THC-treated mice. In the present study we tested whether the same ultra-low dose of THC reverses age-dependent cognitive decline in mice. Old (18-24 months) mice performed significantly worse than young (3-4 months) mice in a battery of cognitive assays, including Morris Water Maze, Passive Avoidance, Y maze, Object Recognition and Place Recognition tests. Old mice that had been injected once with 0.002 mg/kg THC performed significantly better than vehicle-treated old mice, and performed similar to naive young mice in all the assays. The improvement in cognitive functioning lasted for at least 7 weeks following a single injection of ultra-low THC. Sirtuin 1 (SIRT1) is an NAD-dependent protein deacetylase that has been previously shown to be involved in neuroprotection and neuroplasticity. It was found to mediate the protective effects of resveratrol, of melatonin and of caloric restriction, and was suggested to take part in the pathology of various neurodegenerative diseases. In the current study we found that a single injection of 0.002 mg/kg THC elevated the amount of SIRT1-immunoreactive proteins in the hippocampus, the frontal cortex and the cerebellum of old mice for at least 7 weeks. We further hypothesized that such long-lasting behavioral and biochemical changes might be accompanied by structural changes in the brain. Indeed, MRI (Magnetic Resonance Imaging) revealed structural alterations in the brains of old mice 5 weeks after the injection of 0.002 mg/kg THC: Diffusion Tensor Imaging (DTI) detected a lower mean diffusivity, indicating higher tissue density in various brain regions including the entorhinal cortex, amygdala, cingulate cortex and caudate/putamen. T2 relaxation images demonstrated a larger volume of 3 regions (entorhinal cortex, prefrontal cortex and posterior hippocampus) in brains of THC-treated old mice. These findings suggest that extremely low doses of THC, that devoid any psychotropic effect and do not induce desensitization, may provide a safe and effective treatment for mild cognitive impairments in ageing humans. References: (1) Behav. Brain Res. 220, 194 (2011); (2) Exp. Brain Res. 221, 437 (2012); (3) J. Neurosci. Res. 92, 1669 (2014)
1Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 2Department of Developmental Biology and Cancer Research, Hadassah- Hebrew University Medical School, Jerusalem, Israel ; 3Neurology Laboratory, Department of Neurology, Hadassah- Hebrew University Medical Center, Jerusalem, Israel; 4Developmental Psychopathology Laboratory, Department of Psychology, University of Haifa, Israel; 5Cardiovascular Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 6Departments of Psychology and Life Sciences, School of Sciences, Achva Academic College, Be'er Tuvia, Israel ;
Bilateral common carotid artery stenosis (BCAS) models the effects of compromised cerebral blood flow on brain structure and function in mice. We compared the effects of BCAS in aged (21 month) and young adult (3 month) female mice, anticipating a differentially more severe effect in the older mice. Four weeks after surgery there was a significant age by time by treatment interaction on the radial-arm water maze (p=0.014): On the first day of the test latencies of old mice where longer compared with the latencies of young mice, independent of BCAS. However, on the second day of the test, latencies of old BCAS mice were significantly longer than old control mice (p=0.049), while latencies of old controls were similar to those of the young mice, indicating more severe impairment of hippocampal dependent learning by BCAS in the older mice. Fluorescence staining of myelin basic protein (MBP) showed minimal white matter damage in young BCAS mice whereas degradation of myelin was most pronounced in the old BCAS group (p<0.0001). Interestingly, the intensity of MBP signal of old control mice was lower compared with young controls (p<0.05), indicating that old age induces changes in myelin consistency. While microglia morphology was assessed as normal in young control and young BCAS mice, microglia of old BCAS mice exhibited the most striking activation in the area of degraded myelin compared to young BCAS (p<0.01) and old control mice (p<0.05) . These findings show a differentially more severe effect of cerebral hypoperfusion on cognitive function, white matter integrity and inflammatory processes in aged mice. Hypoperfusion may exacerbate degradation initiated by aging, which may induce more severe neuronal and cognitive phenotypes. Supported by: Israel Ministry of Science, Technology and Space, Japan-Israel Scientific Research Cooperation.
1School of Psychological Sciences, Tel Aviv University, Israel; 2Sagol School of Neuroscience, Tel Aviv University, Israel;
Objective: Alcohol use disorder is a chronic relapsing disorder, characterized by preoccupation with obtaining alcohol and a narrowing of the behavioral repertoire toward excessive and compulsive alcohol consumption. Although alcohol use disorder has severe impacts on society, pharmacotherapy is very limited. Fibroblast growth factor 2 (FGF2) plays a role in the development and maintenance of dopaminergic neurons. We recently characterized a positive feedback loop between alcohol and FGF2 in the dorsomedial striatum (DMS). Specifically, we found that alcohol increases Fgf2 mRNA expression, and FGF2 infusion enhances excessive alcohol consumption, whereas blocking FGF2 activity in the DMS reduces alcohol consumption. Thus, blocking FGF2 function may provide a novel therapeutic approach for alcohol addiction. The aim of the present project was to test a translational approach based on this finding. We set out to determine the effects of "compound X", which blocks FGF2 activity, on alcohol consumption. Methods: Rats and mice were trained to consume high levels of alcohol in the intermittent access to 20% alcohol two bottle choice paradigm. "Compound X" was infused directly into rats' DMS or systemically administrated to mice. Results: We found that "compound X" infusion into the DMS reduced alcohol consumption and preference. However, while a low dose of the compound specifically affected alcohol intake, the higher dose had trend towards reducing water consumption as well. In addition, systemic injection of "compound X" to mice reduced alcohol intake and preference. Conclusions: Our findings point to a translational value in targeting FGF2 for treating alcohol addiction.
1Ariel University, Israel; 2Lev Hasharon Medical Center, Israel;
Background: Cannabis use has been reported to negatively affect the course and outcome of various psychiatric disorders, yet little is known on its effect on rates of remission from depression and anxiety disorders and associated clinical and functional outcomes. Methods: In two studies, data was drawn from Waves 1 and 2 of the National Epidemiologic survey on Alcohol and Related Conditions (NESARC), focusing on individuals who qualified for a diagnosis of either Major Depressive Disorder (MDD; N=2,348) or any anxiety disorder (social anxiety, panic disorder, generalized anxiety disorder and specific phobias; N=3,723) at Wave 1. Cannabis users and individuals with Cannabis Use Disorders (CUDs) throughout a four-year period were compared to nonusers in rates of remission, specific psychiatric symptoms, suicidality, general functioning and quality of life at Wave 2, while controlling for baseline confounders. Results: Though rates of remission from MDD and anxiety disorders decreased with level of cannabis use, this was not maintained in adjusted models. Level of cannabis use was associated with significantly more depressive symptoms at follow-up, particularly anhedonia (Adjusted Odds Ratio (AOR)= 2.62; 95% Confidence Interval (CI)= 1.36-5.08) , changes in body weight (AOR= 2.30; 95% CI= 1.33-3.99), insomnia or hypersomnia (AOR= 2.30; 95% CI= 1.29-4.12) and psychomotor problems (AOR= 3.51; 95% CI= 1.95-6.3) . Among individuals with anxiety disorders, aside from specific outcomes (individuals with CUDs were significantly more prone to report breaking up from a romantic relationship (AOR= 3.85; 95% CI= 1.66-8.97) and repeatedly quitting school (AOR= 6.02; 95% CI= 2.65-13.66)), following adjustment no additional differences were found in outcome measures. Conclusions: These findings add to previous reports suggesting that poorer outcome of MDD and anxiety disorders among cannabis users may be attributed mainly to differences in baseline factors and not cannabis use.
1The institue for drug research (IDR), School of Pharmacy, Hebrew University of Jerusalem;
Increase in DA levels in the reward system causes a feeling of euphoria and well-being; therefore, drug use is reinforced regardless of its many adverse consequences and can eventually result in addiction. Since the VTA is the major source for DA in the reward system and because initiation of drug addiction has demonstrated to occur in the VTA, its regulation is of great importance. The VTA receives excitatory and inhibitory inputs, both of which are modulated by acute and chronic exposure to drugs of abuse. As the excitatory inputs to the VTA are well studied, in the current study we focused on the GABAergic inhibitory inputs. Using rat midbrain slices we have previously shown that acute administration of DA or DA increasing drugs inhibited GABAA receptor-mediated IPSCs in VTA DA neurons. Further, we found that DA-induced inhibition involved activation of DA D2-like receptors or GABAB receptors and has presynaptic locus determined by measuring paired-pulse ratio and mIPSCs. However, the use of electrical afferent stimulation in those studies makes the source of the GABAergic inputs to be unknown. In the current study we used optogenetics tools to stimulate the different sources of the inhibitory inputs innervating the VTA emerging from the lateral habenula (LHb), the rostromedial tegmental area (RMTg) and the nucleus accumbens (NAc). We found that in rats injected with ChR2 in the RMTg, DA-induced inhibition of optically evoked IPSCs in VTA DA neurons was strikingly greater than those recorded in response to afferent electrical stimulation (22% and 76% IPSCs inhibition in electric stimulation or optic stimulation of the RMTg, respectively), suggesting that region specificity plays a major role in determining the degree of DA-induced inhibition of DA neurons, eventually controlling DA neuron activity. Currently, we are assessing the contribution of NAc and LHb to DA-induced inhibition. Understanding the means by which DA/cocaine modulates GABAergic inputs to the VTA exerted from different afferent pathways will expand our knowledge about the way drugs of abuse act in the brain and become addictive.
1Department of Molecular Biology, Ariel University; 2Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University;
Recent studies show that social interactions including social inequality, dominance, and social dependence are strongly involved in drug addiction, especially in subordinate individuals who often use drugs as an escape from negative and depressive feelings and stressful situations. The current study made use of selectively-bred stress-resilient, socially-dominant (Dom) and stress-vulnerable, socially-submissive (Sub) mice to investigate the interaction between environmental stress and genetic predisposition to develop addiction to cocaine. In Conditioned Place Preference (CPP) paradigm using cocaine, Sub mice displayed an aversion to drug compared with wild type mice (Sabra), whereas Dom mice displayed drug attraction. Following a 4-week regimen of Chronic Mild Stress (CMS), Sub mice in CPP displayed a marked increase (>400%) in cocaine attraction, whereas Dom mice did not differ in attraction from their non-stressed state. Examination of hippocampal gene expression revealed that CMS alone induced increase in CRF expression in Sub mice (>100%), whereas increases were only seen with cocaine in Dom mice. CMS also universally reduced CRFR1 expression, regardless of drug treatment. Further, CMS-induced decreases in DR1 (>60%) and DR2 (>50%) expression in Sub mice differed markedly from a complete lack of change in Dom mice. Tegmental-hippocampal projections are known to invoke aversion behaviors counteracting limbic drive in response to salient addictive stimuli. Reductions in tegmental-hippocampal tone would alleviate physiological antagonism of mesolimbic circuits. We report here an emerging model of drug addiction which may reside in personality differences with stress-vulnerable individuals developing addictive behavior as a combined result of increased limbic drive and reduced stimulus aversion.
1Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.; 2Analytical Laboratory, Department of Identification and Forensic Science, Israel Police, Jerusalem, Israel.; 3Department of Psychiatry, Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;
In recent years, synthetic cannabinoids have become more popular. These psychoactive substances are designed in attempt to mimic the euphoric effects of the natural cannabis. Novel unregulated compounds appear once older compounds become controlled by law authorities around the world. It has been previously reported that synthetic cannabinoids are not just other forms of Δ9-tetrahydrocannabinol (Δ9-THC); the active component of cannabis. These compounds have chemical structures unrelated to Δ9-THC, different metabolism, and often, greater toxicity. This study aimed to investigate the effects of three novel synthetic cannabinoids and pure Δ9-THC on memory function, exploratory behavior and locomotor activity. To attain these goals we performed a battery of behavioral and motor tests starting 50 min post i.p. injection of each drug to adult ICR mice. The synthetic cannabinoids that were used are AB-FUBINACA, AB-CHIMINACA and PB-22. All synthetic cannabinoids and Δ9-THC caused spatial memory deficits and decreased exploratory behavior as was measured in the Y-maze and staircase paradigm respectively. However, all synthetic cannabinoids but not Δ9-THC demonstrated decreased locomotor activity in the staircase test. Moreover, none of the drugs affected muscle strength and balance in exception of a high dose of AB-FUBINACA which significantly lowered the latency time to fall when mice were suspended on a metal rod with their four limbs. However, when mice were suspended on the rod with their two forelimbs, AB-FUBINACA and Δ9-THC caused a decrease in the latency time to fall. These results suggest varied effects among different synthetic cannabinoids and Δ9-THC. Further studies are needed in order to characterize the overall effects and differences between these synthetic cannabinoids and Δ9-THC such as on anxiety, depression or psychosis-like behavior.
1Adelson Clinic for Drug Abuse Treatment & Research, Tel-Aviv Medical Center ; 2Sackler Faculty of Medicine, Tel Aviv University;
Aims: To study the prevalence of high perceived stress and characterize its risk factors among methadone maintenance treatment (MMT) patients, as stress dysregulation is known to be normalized during MMT. Methods: Random sample of 107 of the current (January 2015) 326 MMT patients were studied using a Perceived Stress Scale questionnaire. History of adverse events, ASI questionnaire, 21-Ham-D rating scale and urine test results were taken. Results: Of the 107 patients, 25% were females. Mean age of opiate use onset was 22.1±7.2, at admission to MMT 41.2±11.0, and current age 50.4±10.8. Mean stress score was 17.6±9.3 (range 0-38), and a high stress level (scored >18) was found among 48.6%. Higher scores were found among the 31 benzodiazepine abusers (24.0±9.1 vs. 15.0±8.1, p<0.0005), and 19 cocaine abusers (22.4±9.5 vs. 16.5±9.0, p=0.01). Scores were higher among 77 patients living alone (18.9±9.2 vs. 14.2±9.0, p=0.02), among 23 patients with history of self-harm (23.0±7.9 vs. 16.3±9.1, F=10.3, p=0.002), 22 patients with history of suicide attempts (23.8±7.9 vs. 16.1±9.0, p<0.0005) and 22 depressed (Hamilton >18) patients (23.6±8.9 vs. 16.0±8.9, p=0.001). Scores did not relate to gender, age (admission or current) and duration in treatment. Logistic regression for high perceived stressed (scored>18) found benzodiazepine abuse (OR= 4.1, 95%CI 1.4-12.0), history of self-harm (OR= 5.5, 95%CI 1.6-18.8) suicide attempts (OR= 3.8, 95%CI 1.1-13.2) and depressed (OR= 3.7, 95%CI 1.1-12.0) to characterize high perceived stressed patients. Perceived stress score was also related to number of current drug abuse and number of adverse events (Corrected mode F=4.6, p<0.0005, Drug abuse F(d.f=2)=7.5, p=0.001; Adverse events F(d.f=2)=4.3, p=0.02). Specifically, the highest score was among patients with more than 2 adverse events and more than 2 drugs abuse and the lowest score was among those with no adverse events and no drug usage. Conclusions: Half of the MMT patients presented high-perceived stress level which was related to their history of adverse events and current drug abuse. The patients' heterogeneity, which most likely precedes treatment admission, may explain the absence of relation between stress level and duration in treatment. A prospective study is needed in order to measure perceived stress changes (reduction) over treatment (parallel to HPA axis normalization).
1Adelson Clinic for Drug Abuse, Treatment & Research, Tel-Aviv Sourasky Medical Center; 2Sackler Faculty of Medicine Tel Aviv University ;
Background: Methylphenidate, an amphetamine-like prescription medication for attention deficit hyperactivity disorder (ADHD) was previously found to be abused among about 15% of our MMT patients. Aims: To evaluate the motives, circumstances and patterns, and the knowledge of patients about methylphenidate indication, effects and risk, and to explain patients about the risk. Methods: Structured questionnaire (scored 0-19) about knowledge and usage of methylphenidate were filled before and following a brief explanation about methylphenidate indication, effects and risk given by patients' therapist. Results: Of the 239 participants, 37.7% reported of lifetime usage. Most of the current participants (95%, n= 227) were previously tested for methylphenidate. Of the 227 participants, 43(18.9%) were tested positive, and 81.4% of these 43 currently reported of “ever used” (only 8 of the previously tested positive, currently reported as “never used’). Before explanation, knowledge score was higher among the ever (10.4±4.1) than the never used (8.9±4.4, p=0.01), improving to the same level following explanation (13.6±4.2, Repeated measured, p<0.0005). The question of methylphenidate effect was correctly answered as stimulant by 76.6% of the ever used compared to only 53.4% of the never used, whom 33.1% incorrectly thought it’s an anxiolytic (compared to 19.5% of the ever used) pain relief/ analgesic/unknown (13.6% vs. 3.9%, p=0.004). Higher proportion of BDZ in urine (58.8% vs. 41.1%, p=0.01) and dual diagnosis (any Axis I 56.6% vs. 41.3%, p=0.03) characterized the current 85 patients who reported of being ever users with no other differences. Conclusion: Education is important to eliminate abuse. However some of the methylphenidate usage seems to be due to self- medication, therefore ADHD diagnosis and treatment is recommended.
1Sagol School of Neuroscience, Tel Aviv University; 2School of Psychological Sciences, Tel Aviv University;
Strong memory associations play critical role in several neuropsychiatric disorders, and are a main cause of relapse in addiction. Thus, disruption of these memories is a powerful treatment approach for relapse prevention. Interference with the process of memory reconsolidation, in which reactivated memories temporarily destabilize and become prone to changes, has been suggested for disruption of pathogenic memories. However, application of this approach in drug-related disorders have yielded mixed results in rodent models, as well as in translation to humans. In addition, the current knowledge on the basic neuronal substrates underlying memory reconsolidation is very limited. Here, we set out to characterize the behavioral and neural mechanisms that mediate alcohol memory reconsolidation. To form cue-alcohol memories, we trained rats to consume alcohol in self-administration procedures for 4 months, and then subjected them to 10 abstinence days. We found that relapse was substantially reduced when the NMDA antagonist MK-801 (0.1 mg/kg) was injected immediately after memory reactivation, suggesting that memory reconsolidation was disrupted. Furthermore, we found this effect to be most robust when memory reactivation involved a change in the number of lever presses required to obtain an alcohol reinforcement. These findings are in line with the hypothesis that efficient destabilization of memories is achieved by their retrieval via surprising/unpredicted consequences (prediction error). Importantly, we found higher levels of neuronal activation in the nucleus accumbens and cingulate cortex after memory reactivation, compared to controls with no memory reactivation, suggesting that these brain regions may play a role in alcohol-memory reconsolidation. Together, our results provide a first step towards mapping of the neural substrates of alcohol memory dynamics.
1Neuropharmacology laboratory, Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel ; 2Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Israel; 3The Laboratory of Biological Psychiatry, Felsenstein Medical Research Center and Sackler Faculty of Medicine, Israel.; 4Geha Mental Health Center, Petah Tikva, Israel;
Ras-related C3 botulinum toxin substrate (RAC), a part of The Rho family of small GTPases is a key regulator of the actin cytoskeleton rearrangement and play important role in dendritic morphogenesis. Cocaine produces neuronal alterations including structural changes in dendritic spine morphology and amount. Here we report that a combination of two FDA approved drugs, opipramol for anxiety and baclofen for spastic movement disorders, have synergistic effect on cocaine seeking behavior in a rat model for cocaine abuse mediated by RAC1. Several previous studies marked sigma-1 receptor as a promising target for prevent craving. Also, sigma-1 receptor binds in a complex with RAC1 gene that regulates a diverse array of cellular events, including synapses formation and morphology changes of dendritic spines. Hence we used a sigma-1 receptor medication (Opipramol) to treat cocaine-addicted rats. We combine it with Baclofen a GABAb (Gabbr1) receptor agonist that was shown to moderately affect craving. In our study, rats were trained to self-administer cocaine (0.5 mg/Kg; FR1) till maintenance, then underwent extinction till abstinence. Opipramol (12.5 mg/kg, i.p) and Baclofen (0.1 mg/kg, i.p) were co-administrated longitudinally throughout the extinction session. Rats were reinstated by i.p. cocaine injection (10 mg/Kg) and drug seeking behavior was monitored. We found that the combination of opipramol and baclofen significantly decreased active lever responding during extinction. Moreover, they also decreased active lever pressing in the relapse test and normalized the RAC1 mRNA levels relative to sham- operated rats. In another experiment, RAC1 inhibitor injected directly to the NAc core decreased active lever presses in the first day of the extinction. We postulate that a combined activation of sigma1 and Gabb1 receptors can suggest a new approach to treat addicts. RAC1 inhibition may play a critical role in decreasing drug seeking and rehabilitation.
1Neuropharmacology Laboratory, The Mina & Everard Goodman Faculty of Life Sciences, Israel; 2The Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Israel;
Aims: Drug addiction is a chronic brain disorder, characterized by the loss of ability to control drug consumption.The mean obstacle in rehabilitation is not the detoxification process but the high rates of relapse that cannot be predicted by any biological or psychological means.Previously, we have found that self-administration (SA) cocaine in a rat model can attenuate neurogenesis in the hippocampus and the neurosteroid DHEA can decrease cocaine craving,parallel to normalization of neurogenesis.In this study we aimed to find a predictive value for relapse by the use of a non-invasive method such as DTI.Methods: Sprague-Dawley rats were trained to SA cocaine (1.5 mg/Kg; FR1) or saline for 1 hour daily until stable maintenance levels were attained.Rats were injected i.p. With DHEA or vehicle 90 mins before exposed to the operant chamber for extinction.MRI was performed followed by DTI analysis of the images. BrdU injected i.p. at day 10 of extinction.The brains were sliced and stained for BrdU & Neun and for s100β.Results: Scanning the rat's brains has shown a marked change in DTI parameters in parallel to their craving and relapse to drug usage.However correlating these measures with neurogenesis showed significance but in an opposite direction.Astrocytes volume was also changed at the end of extinction.These results were correlated with lower cocaine seeking behavior in the relapse test.Discussion & Conclusion:We postulate that cocaine decrease neurogenesis and increase astrogliosis in the DG. DHEA attenuation of cocaine seeking behavior may be due to its beneficial effect on astrocytes that may allow neurogenesis restoration. Moreover ADC measurement demonstrates decrease in total area diffusion in the DG of cocaine SA rats, whereas DHEA treatment normalized ADC values. This can be explained by correlation with astrogliosis and not neurogenesis.The DTI method enables non-invasive examination, which we may predict patient's chances of remaining clean months later
1Tel Aviv University;
Appetitive memories play a crucial role in learning and behavior. Despite their adaptive function, under certain circumstances, they can take a maladaptive form and play a vital part in addiction and similar psychopathologies. In recent years, scientific research demonstrated the ability of memories to be modified following their reactivation, in a process termed memory reconsolidation. In the past years, a few non-pharmacological, behavioral manipulations were tested for their capacity to alter maladaptive memories. With particular relevance to the present work, a recent study showed that induction of aversive counterconditioning (CC) within the reconsolidation process abolished cocaine seeking, in a conditioned place preference mouse procedure. Here, we tested the efficacy of a similar behavioral manipulation in humans. We constructed a three-day experiment: On Day 1, we conditioned computerized contexts (virtual houses) with monetary gain. On Day 2, we retrieved the relevant memory for half of the participants (Retrieval group). Then, all participants underwent CC, where the contexts were re-associated with monetary loss. On Day 3, to reinstate responses formed on Day 1, participants gained money, but without the presentation of any context. We used a binary choice task to measure changes in context preference, induced by the manipulations. Fifty valid participants completed the task in two groups. Choices between houses indicated that using this paradigm, appetitive memories were successfully formed through conditioning, then counterconditioned, and later reinstated. Moreover, we observed reduced reinstatement of the original, appetitive memory, when CC was induced following memory retrieval (p<0.001). We provide here a novel human paradigm that models several memory processes, and demonstrate their attenuation by CC within their reconsolidation. This paradigm can be used to further study complex appetitive memory dynamics and their underlying brain mechanisms.
1Kupchik Lab, Department of Medical Neurobiology, IMRIC, Faculty of Medicine, Hebrew University in Jerusalem;
The mesolimbic pathway consists of several nuclei involved in motivated behavior and has been heavily implicated in motivational disorders, such as addiction. The Ventral Pallidum (VP) emerged in recent years as an important node in the mesolimbic system, integrating mostly inhibitory information from various sources and projecting to areas inside and outside the mesolimbic system. Nonetheless, the VP remains largely unexplored. Thus, the circuit anatomy of different cell populations in the VP have not yet been described properly. Understanding the differences between different populations of VP neurons at the circuit level (inputs and targets) may open a new path for a better understanding of the mesolimbic pathway and its role in addiction. Using the novel TRIO (TRacing the Input and Output) method, we focused on 2 VP projection neuon populations: one projecting to the Ventral Tegmental Area (VTA) , and the other projecting to the Medial Dorsal Thalamus (MDT). In our work we showed anatomycal charecteristic pattern of each microcircuit, identified by shared and varied inputs. Targeting these two main VP populations, projecting to the VTA and the MDT, we have gained a better understanding of the circuits involving brain regions which are known for their relation to addiction and associated to motivated behavior. By comparing their inputs and getting a closer look at the circuits constructing the mesolimbic pathway, we have established a strong foundation for future research on the physiology of the mesolimbic pathway.
1Adelson Clinic for Drug Abuse, Treatment & Research, Tel Aviv Medical Center; 2Sackler Faculty of Medicine Tel Aviv University ;
Background: Methadone Maintenance Treatment (MMT) is the best treatment for opioid addiction. However, many of the opioid addicts abuse stimulants as well. Aims: To compare characteristics and outcome of MMT patients with and without cocaine abuse on admission to MMT. Methods: Study population included all patients admitted to Adelson clinic between June/1993 and June/2015 and stayed at least 3 months. Patients were divided into 4 groups by their cocaine in urine on admission (1st month) and after one year (13th month, or last month if left earlier). Patients' characteristics and long term outcome (up to 23 years) were compared. Results: Of the 790 patients, 23.3% abused cocaine on admission, and more than half of them stopped it during treatment. Specifically, 536 (67.8%) "Never", 100 (12.7%) "Stop", 84 (10.6%) "Always", and 70 (8.9%) "Start" abusing cocaine while in MMT. Comparing the 4 groups, female gender (25.8% of the whole sample) was the most prevalent 36.9%, among the "always" group. Usage opioids of ≥20 years was among 37.4% of the sample, was most prevalent (52.6%) among "always" group. Mean age of admission was 40.9±10 for all sample, but was the youngest (36.2±9.6) at the "Start" group. The "Stop" group had the lowest opioids (22%), and benzodiazepine (51%) abuse after one year, and the highest one year retention rate (93%). They also had the highest methadone daily dosage (147.8±42.6mg/d) that was comparable with the "Always" group (139.5±37.4mg/), however significantly higher than the 2 other groups (119.8±46.1mg/d). Conclusion: The "stop" group had the best retention and opioid abstinence. Those who fail to stop characterized with more years of opioid usage and more females. Higher methadone dose characterized the cocaine abuser, and it seems to be associate with stop cocaine. Half of the cocaine abusers can achieve abstinence with adequate methadone dose that is needed to reduce cocaine and opioids abuse.
1Gal Atlan ,Noa Peretz- Rivlin, Ben Jerry Gonzales, Ami Citri ;
The claustrum is a thin sheet of neurons, hidden between the insula and the striatum. Relative to its volume, the claustrum is the most interconnected structure in the brain, warranting its investigation. Due to its complex structure, very little progress had been made during the past decade regarding its function. Our interest in the claustrum was spurred by the serendipitous identification of a transgenic mouse that enables genetic access to neurons in the claustrum. We identified specific expression of the immediate early gene Egr2 in claustral neurons, allowing us to delicately and accurately manipulate them, thus circumventing the elusive morphology of this structure. Utilizing our unique genetic access, we found that inactivating claustral neurons blocked the development of behavioral sensitization to cocaine, and hindered the performance in selective attention demanding tasks. These results adds up to a number of theories that have been raised regarding the function of this enigmatic brain region. Multiplexed fluorescence single molecule in-situ hybridization conducted in our lab revealed that the EGR2 expressing cells are a sub population of dopamine receptor D1 expressing cells, a finding that sparked our interest in this claustral dopamine reactive ensemble. We performed a real time conditioned place preference experiment using optogenetics in D1-Cre transgenic mice expressing ChR2 in the claustrum and observed a clear preference towards the side of the chamber in which blue light stimulated D1R expressing claustral cells These results begin to unveil distinct molecular characteristics of the claustrum, and create a foothold for further investigation of this mysterious structure’s function in reward and attention behavior.
1The Hebrew University;
Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this talk I will describe recent evidence that suggests a role for central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers’ dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the “medial amygdala network”) that supports social functioning. We also measured the mothers’ behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother’s infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data points to a cortico-striatal dopaminergic mechanism that supports the cognitive processes needed for synchronous human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans are warranted.
1Department of psychology, University of Haifa. ;
The neural mechanisms that facilitate the experience of vicarious social touch are largely unknown. Two neural simulation systems might contribute to processing of vicarious social touch: the inferior frontal gyrus (IFG), which has been previously suggested to be part of a simulation observation-execution neural network and to play a key role in the perception of tactile stimuli and attenuation in the mu\alpha rhythm (8-13Hz), also known as mu suppression, a neural marker that has been related to sensorimotor resonance. In a series of experiments, we found that both the mu suppression over sensory motor cortex, and excitability levels of the IFG are related to vicarious social touch and are modulated by individual levels of empathy. In experiment I, we showed fifty-four participants photos depicting social touch, non-social touch or no touch while their electroencephalography (EEG) activity was recorded. Results showed that highly empathic participants evaluated vicarious social touch as inducing more pleasant emotions and exhibited greater mu suppression upon observation of human social touch compared to less empathic participants. Specifically, both the behavioral and the electrophysiological responses to observed social touch were predicted by levels of personal distress, a measure of emotional contagion. In experiment II, we used anodal transcranial direct current stimulation (tDCS) with forty participants who observed the same photos during tDCS or sham stimulation. The results show that while participants with high levels of emotional empathy showed no change in ratings of vicarious social touch, participants with low levels of emotional empathy rate human touch as more emotional following anodal stimulation of the IFG than following sham stimulation. Combining the findings from the two experiments we reasoned that vicarious social touch is facilitated through known simulation mechanisms but is differentially affected by levels of empathic traits.
1Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.; 2Department of Psychology, School of Sciences, Achva Academic College, Be'er Tuvia, Israel;
Chronic stress (CS) induces cognitive enhancement in young adult female mice, while its effects on old females are mainly impairing. Focusing on male mice enables us to reveal similarities and dissimilarities compared with our previous results with females. Young adult (3 months) and old (20 months) C57BL male mice were exposed to chronic stress (CS) or control conditions for 5 weeks, after which they underwent extensive behavioral testing while continuing exposure to CS. CS consisted of psychological stressors delivered weekly, in random order. CS induced significant weight loss in old but not young adult mice, reflected by a triple interaction of age, CS, and time (p=0.04). Age by CS interaction was also demonstrated in stress-induced hyperthermia (p=0.024), indicating that CS increased the response to acute stress in young adult mice and blunted the response in old mice. CS increased the amount of time young adult but not old mice spent in the center of the open field (p=0.023). This interaction may reflect reduced anxiety of CS-exposed young adult mice. Both age (p<0.0001) and CS effects (p=0.002) were found in the radial-arm water maze. Old mice displayed longer latencies compared with young adult mice (p<0.0001), while CS mice displayed shorter latencies compared with control mice (p<0.0001). Taken together, these results suggest that chronic stress induces different outcomes in young adult and old male mice, similar to our observations in females. Young mice appeared resilient to CS, whereas old mice displayed resilience on some aspects and vulnerability on others. It still needs to be elucidated whether CS induced differential effects on brain mechanisms as we have previously observed in female mice (reduced dentate gyrus volume, increased hippocampal BDNF and miR375 expression). Supported by a grant from the Israel Ministry of Science, Technology and Space, Japan-Israel Scientific Research Cooperation Program.
1Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 2Department of Developmental Biology and Cancer Research, Hadassah- Hebrew University Medical School, Jerusalem, Israel ; 3Developmental Psychopathology Laboratory, Department of Psychology, University of Haifa, Israel;
Late life depression (LLD) is an age dependent phenomenon that is thought to be influenced by environmental stress and is frequently accompanied by anxiety and cognitive decline. A key question for experimental evaluation is whether stress-related effects on affective, cognitive and molecular phenotypes are indeed age related. We investigated this question in female C57BL/6 mice aged 3 (young) and 23 (old) months that were subjected an 8 week chronic stress (CS) protocol. In the final 3 weeks a battery of cognitive-behavioral tests was administered to evaluate CS effects. Old females were more vulnerable to the effects of CS than young females, showing reduced weight and hyper locomotion in the open field. Young females showed reduced anxiety like behavior and enhanced cognitive functioning, contrary to old females that did not benefit from the stress. These finding were correlated with histological studies. These showed that in young females CS caused an increase in hippocampal dentate gyrus (DG) BDNF levels, and in DG area while old mice did not show such CS effects. Another correlation for the differential effects of CS across age was found in hippocampal miRNA expression analysis; expression profiles in CS exposed young females were significantly higher than in CS exposed old females and there was a specific increase in miR-375. Thus, our studies demonstrated differential behavioral effects of CS across age. Young females may actually benefit from stress, while in old females there are negative effects. The molecular correlates we observed could be related to the age dependence of stress modulated neuropsychiatric disorders. Supported by: Israel Ministry of Science, Technology and Space, Japan-Israel Scientific Research Cooperation
1sackler school of medicine tel aviv university; 2Weizmann Institute of Science; 3interdisciplinary center herzliya;
Background The dynamics of global network connectivity following Methylphenidate treatment highlight the circuitry dysfunction of individuals with ADHD. We present a double blind cross-over placebo controlled study in which 20 youths with ADHD were recruited for two test days and 20 controls were recruited for one test day. A neuro-cognitive computerized attention response task battery was administered twice in each test day while simultaneously measuring EEG. In the study group, the second battery of each test day was administered one hour after ingestion of Placebo/ Methylphenidate - alternately. In the Control group, the second battery was administered after a one hour break. Results ERP analysis revealed significantly lower P300 (250ms-400ms) mean amplitude (MA) in Methylphenidate compared to Placebo in frontal regions. Significantly lower standard deviations of the response times (SDRT) were measured for Methylphenidate compared to Placebo conditions. SDRT also correlated strongly (>0.7) with the P100 (50ms-200ms) MA of the Placebo condition, again in frontal regions. Furthermore, clinical scores of Inattentiveness strongly correlated (>0.7) with the P100 MA of the Methylphenidate condition in frontal regions. Network analysis revealed higher mean clustering coefficient (MCC) around P300 under Placebo conditions compared to the Methylphenidate treatment. Conclusions We found that Methylphenidate treatment affects the amplitude of the EEG signal in frontal regions during a cognitive task. Prediction of clinical symptoms and performance of ADHD can be obtained from the EEG amplitude. Furthermore, network analysis of the EEG data allows us to go beyond the electrode level and observe a global effect of Methylphenidate on the ADHD brain, which can be evaluated using simple network measures.
1Ness ziona mental health center; 2Weizmann institute; 3Interdisciplinary center; 4Sheba medical center;
Background: Attention and hyperactivity disorder (ADHD) has long been thought to reflect circuitry dysfunction. Recently it has shown that there is abnormal widespread brain networks dynamics in individuals with ADHD. However, data about global network connectivity dynamics after methylphenidate (MPH) treatment is lacking. Project aim: To evaluate MPH effect on global network connectivity dynamics in youth with ADHD. Design and methods: Double blind cross-over placebo controlled study. Twenty youths with ADHD and age and sex matched controls were recruited. Neurocognitive computerized tasks battery was administered for each subject twice in one day while simultaneously measuring EEG. In the study group, the second battery of each test day was administered 1 hour after ingestion of Placebo/MPH - alternately. Control group second battery was administered after 1 hour break. Data preprocessing and artifact correction was made using EEGLAB. Network analysis was made using matlab. EEG data and network analysis was made for the data recorded during the Sustained attention response task (SART). Results: Significantly higher scores were measured after MPH treatment compared to placebo within all tasks. Control group revealed significantly higher commission scores ("No-Go" precision) on the second trials in the SART. Global efficiency was significantly lower on second trials in the control group. Same network analysis in the ADHD group revealed significantly higher global efficiency after placebo and no significant change in global efficiency after MPH treatment. Significant post-stimuli global efficiency change from baseline was observed in all conditions. These differences were prominent 900ms following the cognitive stimuli before returning to baseline. Conclusions: We found inverted network patterns in ADHD patients during high cognitive demanding tasks. This network pattern inversion was moderated after MPH treatment, suggesting an MPH effect on ADHD related global connectivity dynamics. These network alterations were time sensitive and may reflect flexibility moderation of the network underlies MPH effect on attention in ADHD.
1Departments of Behavioral Sciences, The Center for Psychobiological Research, The Max Stern Yezreel Valley College; 2Department of Psychology, Tel Hai College; 3Pediatric Hematology Unit, Emek Medical Center, Afula; 4The Ruth and Baruch Rappaport School of Medicine, Technion, Israel Institute of Technology, Haifa;
Background: Beta thalassemia major (β-TM) is an inherited hemolytic anemia. Patients with β-TM are transfusion-dependent for life, and develop iron overload with impaired function of vital organs. They are also at risk of developing cognitive and neural impairments. The aim of the present study was to assess cognitive function and to identify potential alterations in scalp-recorded Event-Related Potentials (ERPs) in adults with β-TM compared with matched healthy controls. To date, ERP studies in the field of β-TM are scarce and limited to children. Methods: β-TM patients and healthy controls (n=17 and 25, respectively) participated in the study (age > 18 yr). Attention and response inhibition function and ERPs were examined using a stop-signal task in which participants have to quickly and effectively respond to frequent Go stimuli while withholding their response when a Go stimulus is immediately followed by a stop sign. The ability to inhibit inappropriate or irrelevant responses (i.e. response inhibition) requires a fast control mechanism that prevents the execution of the motor response, and considered a hallmark of executive function control. EEG was recorded continuously using a 64-channel HydroCel Geodesic Sensor Net. Correlations between task performance, ERPs and hemoglobin levels were also examined. Results: results showed impaired cognitive performance in β-TM patients, as indicated by longer response times than controls to both Go stimuli and Stop signal stimuli. Hemoglobin levels were negatively correlated with response times to Go stimuli. Electrophysiological results indicated significant alterations in peak amplitudes of several ERP components; β-TM patients, relative to controls, had greater P1 and P2 to Go stimuli and greater P1, N1 and P300 to Stop signals. Significant moderate to strong correlations were found between hemoglobin levels and amplitude of all ERP components; the lower the hemoglobin level, the greater (more pronounced) the ERPs amplitude. Conclusions: our results indicate impaired attention and response inhibition function in β-TM patients, accompanied by significant alterations in neural activation. The present study represents a novel investigation of cognitive function and related brain dynamics in β-TM in adult. Integrating neurophysiologic and neuropsychological assessment and interventions, designated for adults, into traditional disease management, may be imperative in achieving a better quality of life for these patients.
1University of Haifa;
Models of emotional processing highlight the interactions between emotional and attentional systems. These views are based on evidence that emotional information is prioritized and impact attentional functions, as well as evidence that attention and control mechanisms mediate reactions to aversive stimuli. Most of the views today suggest a balance between bottom-up emotions, triggered automatically by limbic regions, and top-down regulation by cortical regions. However, our findings suggest the existence of bottom up (not only top-down) control. In this talk, I will present evidence that attention mechanisms and anxiety-related personality traits and tendencies modulate behavioral, neural and autonomic (basic motor-related blood pressure) reactions to highly-negative material. This evidence suggests that individual characteristics shape the connectivity within a neural network that is involved in the reactions to emotional stimuli; activation in this neural network is further modulated by attention. These findings have possible clinical implications for individuals that show dysfunctional reactions to emotional stimuli.
1Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.; 2Department of Psychology, School of Sciences, Achva Academic College, Be'er Tuvia, Israel;
The Ahi1 gene has been associated with several psychiatric disorders. We have previously demonstrated reduced anxiety of Ahi1+/- mice under basal conditions. The present study was designed to test the role of Ahi1 in responsiveness to chronic stress (CS) using behavioral and histological outcome measures. The sucrose preference test was used to evaluate the efficiency of CS. Only Ahi1+/+ mice displayed reduced sucrose preference (SP) following CS, reflected by a significant effect of genotype (F(1,21) = 6.593, P<0.05) on two-way ANOVA . Post hoc comparisons indicated that CS reduced SP in Ahi1+/+ mice compared with Ahi1+/+ controls (p<0.05) but had no such effect in Ahi1+/- mice. Stress-induced hyperthermia tested the effect of CS on an acute stress response. CS induced a blunted response in Ahi1+/+ mice but had no effect on Ahi1+/- mice, as reflected by triple interaction of genotype, treatment, and time (F(1,63) = 5.001, p<0.05) on two-way ANOVA with repeated measures. In the open field test CS increased the amount of time Ahi1+/+ mice spent in the center of the arena, but had no effect on Ahi1+/- mice, reflected by significant exposure by genotype interaction on two-way ANOVA (F(1,70)=6.21, p<0.05). Testing for neurogenesis, doublecortin straining revealed an increased rate of newly formed neurons in Ahi1+/+ mice following CS, but no similar effect on Ahi1+/- mice, reflected by a main effect of genotype (F(1,23)=6.189, p<0.05) and marginal genotype by exposure interaction (F(1,23)=4.129, p=0.054). Post hoc comparisons indicated increased neurogenesis in Ahi1+/+ mice following CS compared both with Ahi1+/+ controls (p<0.05) and Ahi1+/- CS (p<0.01). Taken together, these results indicate that not only do Ahi1 deficient mice manifest a basal anxiolytic-like phenotype, they are not responsive to CS, suggesting that Ahi1 is involved in detection of fear-inducing stimuli. Supported by a grant from the ISF in the context of a cooperative research program with NNSFC
1Psychology Department and the Integrated Brain and Behavior Research Center, University of Haifa;
Anxiety disorders typically emerge during childhood, and may reflect perturbed neurodevelopment (Pine, 2009). Yet, developmental differences in risk, onset, and maintenance of anxiety disorders are poorly understood. Methods from neuroscience permit the study of specific neuro-cognitive systems, and thus may be used to reveal the underling mechanisms of anxiety. This talk will focus on two mechanisms related to information-processing functions: threat-related-attention biases and fear conditioning and extinction. In the first part of the talk, data from several fear conditioning studies conducted in anxious and non-anxious youth will be presented. Specifically, the effects of anxiety and age on amygdala and prefrontal cortex activation and connectivity will be presented. In the second part of the talk, data from studies focusing on threat-related attention biases will be reviewed. This will include data from a unique at-risk for anxiety sample of 9 year old children who completed a dot-probe task examining attention bias to threat while in the fMRI scanner. The discussion will integrate findings from both lines of research, and highlight the distinctive contribution that developmental cognitive neuroscience research can make towards identifying early biological markers of anxiety. Identifying these indicators is critical to developing interventions that target the cognitive mechanisms implicated in anxiety disorders.
1The School of Psychological Sciences, Tel Aviv University; 2Sagol School of Neuroscience;
Although recent conceptual models highlight that emotion regulation (ER) is a complicated process that involves several regulatory stages, empirical studies have focused on an implementation stage involving actual execution of regulatory strategies. Little is known about a post-implementation regulatory stage, which involves monitoring an implemented regulatory strategy across time. In this stage, a particular regulatory strategy is implemented on a particular stimulus that differs in its emotional intensity. Specifically, distraction involves disengaging attention from emotional stimuli by producing unrelated neutral thoughts. By contrast, reappraisal involves engaging attention with the emotional stimuli by producing less negative interpretations. The combination of emotional intensity (high, low) and a regulatory strategy (distraction, reappraisal) constitutes regulatory preferences. Most broadly, in low intensity individuals prefer reappraisal over distraction, because whereas both strategies equally modulate emotion, only reappraisal offers long term benefits. In high intensity individuals prefer distraction over reappraisal because distraction more strongly modulates emotion. The present study examined how regulatory preferences influence post-implementation choices, and the short-term neural consequences of these choices. 28 participants implemented distraction or reappraisal on an image of high or low intensity, and then chose whether to maintain or switch. To uncover short-term neural consequences, we measured the Late Positive Potential (LPP), an electro-cortical component that is attenuated during successful ER, following choice. We expected and found that regulatory preferences strongly predicted choice to maintain the initial implemented strategy. Furthermore, only in high intensity, when distraction is both more preferred and more effective relative to reappraisal, regulatory preferences were associated with adaptive short-term neural consequences.
Empathy represents a fundamental ability that allows for the creation and cultivation of social bonds. As part of the empathic process, individuals use their own emotional state in order to interpret others’ emotions and to accurately judge their intensity. Termed by Carl Rogers, empathic accuracy is the moment to moment change in one's ability to recognize the intensity of others' specific thoughts and feelings. In study one, we show that exposure to stimuli designed to elicit empathy hinders accurate valence recognition of facial expressions, thus demonstrating a bias in recognition of emotional facial expression as a function of empathy for pain. In study two, we further examine whether this bias can be modulated by emotional desensitization, a numbing or blunting of emotional reactions to events which would typically elicit a strong response. To this aim, we assessed the effect of exposure to short films depicting violence from the media on judgments of the intensity of pain in facial expressions.
1Department of psychology, University of Haifa, Israel; 22) Department of computer science and applied mathematics, Weizmann Institute of Science, Israel;
We study how human groups synchronize common movements. Human or animal group movements arise from the actions of each group member, and reflect the group's social and communication patterns. We examine how emerging spatiotemporal movement patterns reflect individual characteristic of the group members, especially their empathic tendencies. We rely on two observations regarding animal group behavior. The flocking patterns of birds suggest that a bird's social position in the hierarchy determines its flight direction, leading or following other birds' directions [Nagi et al., 2010]. In fish, local relations between individuals may define their direction and lead to swarming behavior [Paley et al., 2007]. Our experiment examined whether the basic principles of collective animal behavior may shape how human groups move. Importantly, we were also interested in examining spatial patterns of human group movements is determined by the empathic tendencies of the group. We let 30 groups of 4 subjects play a computer game. Each subject used four arrows to move a circle inside a common square arena, while seeing the movements of the 3 other players. Additionally, all subjects filled in the empathy questionnaire. We tested whether group members interact with others differently according to the distances between their circles. The distances between group members define a time-dependent communication network structure that yields a natural definition of a group's synchronicity measure [Paley et al., 2007]. We present preliminary findings; synchronization between humans may depend on their relative distances. Interestingly, individuals with a high empathy score moved their circles nearer to others'. This suggests that traits of the individuals forming a group, such as their empathic tendencies, come into play when a collective animal-like synchronization behavior emerges.
1Department of Behavioral Sciences, Ariel University; 2Clinical Research Center for Brain Sciences, Herzog Medical Center;
Recent reviews of transcranial direct current stimulation (TDCS) influence on working memory (WM) show limited support for the initially cited enhancing effect, and highlight the need for future research aimed at investigating the specific circumstances to optimize stimulation outcomes. Social stress, mediated by pre-frontal cortex activity similarly to WM, and influenced by TDCS as well, might be an important parameter interacting with TDCS effect on WM. The purpose of the present study was therefore to examine the interaction between social stress and TDCS effects on WM in a healthy cohort. One hundred and six healthy students were randomized to one of four study group: TDCS+STRESS, TDCS+noStress, sham+STRESS, sham+noStress. Stress was manipulated using the Trier Social Stress Test. Working memory was measured using a modified verbal n-Back task. Questionnaires and saliva cortisol level tests were used to quantify stress reaction. The main results of the study were (1) unilateral TDCS to the dlPFC did improve executive attention compared to sham, but (2) a statistically significant interaction was found between TDCS and stress: participants who went through stimulation under social stress showed an impairment in executive attention. The results have important implications on our understanding of dlPFC role in stress and cognitive management as well as on the limitation of the use of TDCS as an enhancement tool in healthy population.
1Tel Aviv Soarasky Medical Center, Tel Aviv Center of Brain Function ;
For the past few decades, pharmacological therapy has been the primary method for treating mental disorders, and the focus of an intense research. Nevertheless, current psycho-pharmacological treatments are considerably restricted by the fact that drugs unselectively reach both pathologically relevant as well as irrelevant brain regions, thus causing adverse drug reactions (side effects) along with the desired therapeutic effects. In addition, it is known that contextual physiological and psycho-physiological factors, such as a patient's environmental setting (Swanson et al. 2002) and diet (Schmidt & Dalhoff, 2002) significantly interact with the pharmacokinetic properties and efficacy of a drug. In light of the interaction between treatment outcomes and its contextual factors, it is plausible to assume that one could improve a psycho-pharmacological treatment by administering a drug, while inducing an advantageous physiological state in brain regions that interact with the drug's active ingredients (by selectively manipulating its pharmacokinetic\dynamic properties), and that the induction of such state could be achieved with a certain kind of a behavioral task. Specifically, we speculated that a task which regulates blood flow and blood volume in a drug's sites of action should facilitate an amplification of drug deliverance and absorption. The concept of coupling drug administration with a functional task which activates therapeutically relevant brain regions was coined "Functional Pharmacology". In order to investigate the Functional Pharmacology concept, 24 ADHD patients participated in a three-session within-subject, single-blinded experimental design. Following administration of a weight-adjusted dose of Ritalin IR™ (active ingredient – Methylphenidate (MPH)), subjects either "Up" (experimental condition) or "Down" (control condition) regulated their right-Inferior Frontal Gyrus (an area that mediates executive functions and one of MPH's sites of action) BOLD activity via a real-time fMRI Neurofeedback task. Since BOLD signal is indicative of regional blood flow and blood volume which accompany neuronal activity, its up\down regulation could lead to higher\lower drug delivery and reactivity in the sites of action, respectively. Cognitive performance was evaluated before and after the coupling of drug administration and the consecutive neurofeedback task. We hypothesized that following the coupling of MPH administration and rIFG up regulation neurofeedback, cognitive improvement would be higher than following the coupling of MPH and rIFG down regulation. More importantly, we speculated that regardless of the experimental conditions, rIFG BOLD activity during the neurofeedback task would be predictive of cognitive improvement (i.e. a positive correlation between r-IFG BOLD percent signal change during the neurofeedback task and the improvement in cognitive performance). In accordance with our assumptions, improvements in two measured cognitive functions, sustained attention and response inhibition, were substantially larger following the up regulation condition than following the down regulation condition. Additionally, subjects successfully up regulated their rIFG, and gradually learned to down regulate it as well. Even though behavioral results did not survive standard correction for multiple comparisons, we found a significant positive correlation between averaged rIFG BOLD activity and the mean subjects' improvement in sustained attention. Our results confirm that manipulating designated brain regions that interact with an administered drug is achievable in a relevant clicnical population, and that therapeutic effects may be altered by conducting a functional task following drug administration. Taken together, we interpret these findings as an exemplary manifestation of a novel approach, the Functional Pharmacology concept, which may pave a way for the amplification and exactitude of pharmacotherapy, for ADHD as well as for other mental disorders.
1Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Israel; 2MRI Lab, The Human Biology Research Center, Department of Medical Biophysics, Hadassah Hebrew University Medical Center; 3Department of Psychiatry, Hadassah Ein-Kerem Hospital, Israel; 4Department of Psychology, The Hebrew University of Jerusalem, Israel;
We here present the effect of gender on the neural encoding of emotions by large-scale functional connectivity networks. Previous research has demonstrated an effect of gender on regional brain activations in response to emotional stimuli. However, no study to date has examined the influence of gender on the synchronization between remote brain regions in response to different emotions. Synchronized oscillatory neural networks are viewed as a mechanism for generating cerebral integration, which is thought to play a key role in the formation of emotions. Here, 40 young healthy Israeli students (20 females, 20 males) underwent an fMRI scan. Each scan included induction of sustained emotional states (10 minutes each) of sadness, happiness and a neutral state using film clips. Gender differences are examined for each functional connectivity network of each emotion and possible clinical relevance of the findings is discussed.
1Techion - Israel Institute of Technology;
Considered an antidepressant and anti-anxiety agent, Hypericum perforatum affects multiple neurotransmitters in a non-competitive synergistic manner, and may have nootropic potential. We quantitatively reviewed the pre-clinical literature to examine if there is a cognitive-enhancing effect of H. perforatum in healthy rodents. Additionally, within these studies, we compared the effects observed in intact rodents versus those whose performance has been impaired, mostly through stress manipulations. The meta-analysis incorporated studies that examined the effect of H. perforatum versus placebo on memory indices of task performance. All analyses were based on weighting different studies according to their inverse variance. Thirteen independent studies (published 2000-2014) involving 20 experimental comparisons met our inclusion criteria. The results showed a large positive effect of H. perforatum on cognitive performance for intact, healthy rodents (d = 1.11), though a larger effect emerged for stress-impaired rodents (d = 3.10 for restraint stress). The positive effect on intact rodents was observed in tasks assessing reference memory as well as working memory, and was not moderated by the type of memory or motivation (appetitive versus aversive). Thus, while primarily considered as a medication for depression, H. perforatum shows considerable nootropic potential in rodents.
1Department of Psychology, University of Haifa; 2The Integrated Brain and Behavior Research Center (IBBR), University of Haifa;
In real life people are often forced to make critical decisions under stress. Behavioral observations and experimental data suggest that psychological stress affects the quality of decision making, potentially leading to sub-optimal choices. Decision making in the context of monetary reward has been excessively studied by the use of the Delay Discounting (DD) task during which participants make choices between a small immediate vs. a larger delayed monetary reward. This work established that individuals differ in their tendency to discount the value of a reward as a factor of the delay to obtaining it, and that larger discounting of future rewards may be regarded as a behavioral measure of impulsivity. Interestingly, studies examining the effect of stress on DD reported mixed results, including more impulsive behavior under stress, less impulsive behavior, or no effect at all. One possible explanation for such inconsistency may relate to the fact that previous studies overlooked potential differences in individual’s innate tendency to discount future reward, as well as in the impact of stress on decision making in the context of impulsivity. In order to address this critical gap in the literature we conducted a within-subject examination of impulsivity and stress interaction. To this end, 18 healthy females completed the DD task before and after undergoing an acute laboratory stress induction. Saliva samples and self-report affect measures were collected at 4 time points throughout the experimental session. Corresponding our hypotheses, change in impulsivity scores from before to after the stress greatly differed across participants with half of our participants exhibiting more impulsive behavior after the stress while the other half showing the reversed pattern. Interestingly, participants who were more impulsive after the stress also showed a tendency towards more negative affect, suggesting the stress induced impulsivity may indicate sub-optimal choice selection.
1University of Haifa;
Essential hypertension (EH) is an important risk factor for cerebrovascular diseases and a major cause of premature death in industrialized societies. A predisposing factor for EH is prehypertension: blood pressure (BP) values at rest that are at the higher end of the normal range. Similar to patients with EH, prehypertensives already show abnormal vascular and heart rate reactivity to stressing stimuli. However, daily life contains many more situations of mild aversive emotions than those involving highly aversive stress. Therefore, abnormal reactivity to mild negative emotion stimulation may constitute an important risk factor for future development of cardiovascular dysfunction. We compared the BP responses to neutral and negative pictures between prehypertensives and normotensive controls. BP reactions were analyzed in a continuous fashion, in contrast to previous studies that averaged BP responses across blocks. The innovative nature of this study required new pre-processing and analysis tools, including specific artifact corrections and non-linear regression models. Our findings showed that both prehypertensives and normotensives exhibited lower BP levels in response to negative compared to neutral pictures, replicating previous results with healthy participants. Furthermore, compared to controls, prehypertensives reacted with a steeper and larger decline in BP levels following negative pictures, followed by longer recovery to baseline levels. To the best of our knowledge, this is the first study to examine BP reactions to mild emotional stimuli among prehypertensives. Considering the high frequency and health risks related to prehypertension, understanding the autonomic reactions to emotional stimuli in this population is of clinical importance. Knowledge derived from this study is further important in order to better understand autonomic reactions to emotions in different populations exhibiting dysfunctional emotions such anxiety or depression.
1Laboratory of Biological Psychiatry, Felsenstein Institute Campus Rabin and TAU; 2Laboratory of Transplantation,Felsenstein Institute Campus Rabin and TAU; 3Laboratory of Diabetes and Obesity Research, Felsenstein Inst.Campus Rabin, and TAU;
Background: Recent work has highlighted the role of brain insulin on memory and mood. Intranasal insulin delivery was conducted in several clinical studies in Alzheimer's disease (AD) patients with modest efficacy.Objectives: 1. Create a physiologically regulated insulin delivery to the brain by intracranial pancreatic islets transplantation. 2. Assess the capacity of the intracranially grafted islets to attenuate behavioral dysfunctions in rat models of cognitive impairment. 3. Determine the effect of the grafted islets on brain insulin level and on peripheral metabolic parameters. Methods: Inbred adult Lewis rats were used. One group of rats were treated for 3 days with MK801 (0.15mg/kg ip) or vehicle. A second group was treated with a single icv-STZ (3 mg/kg) administration to create AD model. Half of the rats were transplanted with syngeneic pancreatic islets, grafted into the cranial subarachnoid cavity. Spatial memory was assessed 6 weeks post transplantation using the Morris Water Maze (MWM) test, and locomotion by the Open Field (OF) test. Metabolic effects were studied by analysis of brain and peripheral insulin and glucose levels. Results : Islets transplantation in rats significantly increased brain (frontal cortex and hippocampus) insulin levels without affecting blood glucose. In the OF test, rats with grafted islets were not different in motility parameters compared to intact controls. In the MWM paradigm, MK-801 treated rats and icv-STZ treated animal showed marked impaired spatial memory, and grafted islets significantly corrected it. Moreover some of the icv-STZ treated rats presented obesity accompanied by hyperinsulinemia, and this metabolic effect was reversed by the grafted islets. Conclusion: Brain grafted islets increase level of brain insulin without alteration of glucose homeostasis, and attenuate cognitive and metabolic dysfunctions in rat models of AD, and in rat model of cognitive impairment due to hypoglutamatergic state.
1Psychology Department, University of Californai, Berkeley; 2Tel Aviv Sourasky Medical Center, Functional Brain Center, Tel Aviv, Israel; 3Department of Psychology, University of Haifa, Haifa, Israel; 4Center for the Study of Emotion and Attention, University of Florida, Gainesville, Florida , USA; 5Blavatnik School of Computer Science, Tel-Aviv University, Tel Aviv 69978, Israel; 6Sagol school of Neuroscience, Tel Aviv University, Tel Aviv, Israel; 7Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;
Sleep deprivation has been shown to alter emotional processing possibly associated with reduced frontal regulation. Such impairments can ultimately fail adaptive attempts to regulate emotional processing (also known as cognitive control of emotion) though this hypothesis has not been directly examined. We therefore explored the impact of sleep deprivation on two different cognitive-emotional paradigms, recorded using fMRI and EEG. Both paradigms involved task-irrelevant emotional and neutral distractors presented during a competing cognitive task, thus creating a continuous demand for regulation of emotional processing. We further examined changes to the connectivity patterns of emotional networks prior to these tasks (i.e. during rest) to assess the impact of preexisting alterations in connectivity induced by sleep loss. Results reveal that while participants showed enhanced limbic and electrophysiological reactions to emotional distractors regardless of their sleep state, they were specifically unable to ignore neutral distracting information following sleep deprivation. As a consequence, sleep deprivation resulted in similar processing of neutral and negative distractors thus disabling accurate emotional discrimination. Such abnormal emotional reactivity was further predicted by changes in resting state connectivity of the limbic network, recorded prior to task performance. Furthermore and in accordance with our predictions, sleep deprivation triggered a decrease in prefrontal connectivity patterns in both EEG and fMRI tasks, reflecting a profound decline in cognitive control of emotion. Notably, such a decline was associated with lower REM sleep amounts, supporting a role for REM sleep in affective imbalance. Altogether, our findings suggest that losing sleep impairs emotional reactivity by lowering the threshold for emotional activation and that these changes can further be detected in the intrinsic connectivity of the sleep deprived brain. Such maladaptive loss of emotional neutrality can provide a novel mechanism by which disturbed sleep can bring about the development of anxiety.
1Tel Aviv Center for Brain Functions, Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center; 2School of Psychological Sciences, Tel Aviv University; 3National Institute of Mental Health, USA; 4ElMindA Ltd.; 5Sagol School of Neuroscience, Tel-Aviv University;
Introduction: Attention Deficit Hyperactivity Disorder (ADHD) is hallmarked by deficits in response inhibition and sustained attention. Numerous fMRI and EEG studies have revealed the right inferior frontal gyrus (rIFG) as one of the underlying neural mechanisms associated with these deficits. Previous studies have shown that applying transcranial direct current stimulation (tDCS), a safe non-invasive method, while performing a task that requires response inhibition can improve performance. In this study we combine these techniques with the hope to achieve a more comprehensive model of ADHD, enabling a prediction for treatment success. Methods: Nine patients clinically diagnosed with ADHD were included in this study. The protocol consisted of pre and post-treatment EEG-fMRI scans measuring rIFG activity followed by 13 treatment sessions as well as pre and post behavioral assessments using the standard ADHD continuous performance task (CPT). Every third treatment session was conducted with EEG and tDCS. Patients were asked to complete a Stop Signal Task (SST) while under stimulation and a Go/NoGo task following stimulation. The remaining two thirds of the treatment sessions were tDCS only and asked the patients to perform the SST under stimulation. The stimulation protocol included 20 minutes of HD-tDCS (max current of 1mA) with five 1mm Ag/AgCl electrodes placed in a montage targeting the rIFG. Results: Analysis of the CPT revealed a significant decrease in reaction time standard deviation following treatment (p=0.01). Task improvement was found to be positively correlated with rIFG activation measured during response inhibition from a different task performed in the pre-treatment fMRI scan (r=0.76, n=6, p=0.07). Conclusion: This study suggests that sustained attention in ADHD can be modulated by rIFG electrical stimulation. These preliminary results demonstrate the potential clinical efficacy of combining stimulation with multi-modal monitoring for ADHD treatment.
Synaesthesia is a condition in which a specific sensory dimension (inducer) elicits another sensation not commonly associated with it (concurrent). Synaesthetes may experience a specific colour when listening or thinking of numbers or letters. Large-scale behavioural studies have provided a rich description of the different synaesthesia phenotypes. Recently, great amount of research has been oriented to uncover whether a single or multiple brain mechanisms underlie these various types of synaesthesias. Interestingly, most of the synaesthetic inducers are conceptual stimuli such as numbers, letters, months and weekdays. Emotion is an important component associated with these conceptual inducers as synaesthetetes may report emotion displeasure when experiencing stimuli, which are incongruent with their association. We studied the anatomical correlates of specific conceptual inducers and their possible impact in emotion-related brain areas. We used Voxel-Based Morphometry (VBM) to compare grey matter (GM) volume in synaesthetes and non-synaesthete controls. Increase in GM was found in areas coding the semantic aspect of numbers (left angular gyrus) and in emotion related areas (amygdala and anterior cingulate cortex). These findings are discussed in line with current neurobiological models of synaesthesia.
1Sackler Faculty of Medicine, Tel Aviv University, Israel; 2The Behavioral Neurogenetics Center, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Israel;
Background: The 22q11.2 deletion syndrome is the most common known genetic risk factor for the development of schizophrenia. The main goal of this study was to describe longitudinally the subthreshold psychotic syndrome and neurocognitive development in 22q11DS individuals. Additionally, we wished to identify the neurocognitive deficits that predict subthreshold psychotic syndrome. Method: A longitudinal design was implemented at 2 time points (14.7±2.1 months apart), and included 44 participants with 22q11DS, 19 with Williams syndrome (WS) and 30 typically developing controls (TD), age 12 to 36. Evaluation concluded standardized psychiatric measured and the computerized neurocognitive battery (CNB). Results: At baseline, individuals with 22q11DS, had the highest rates for subthreshold negative syndrome, compared to individuals with WS and TD.There was no significant effect of time on neurocognitive domains only for group, 22q11DS was found to have higher efficiency scores than WS, while TD controls had better performance compared to both groups. At baseline, individuals with 22q11DS but not those with WS, showed significant association between the presence of negative subthreshold psychotic and general neurocognitive performance (GNP), Executive Function and Social Cognition domains. In 22q11DS, deficits in GNP and younger age at baseline, predicted negative subthreshold psychotic syndrome at follow-up. Finally, 22q11DS individuals under medication showed more improvement in GNP efficiently score between baseline and follow-up. Conclusions: Our data suggest that neurocognitive deficits are associated with negative subthreshold psychotic syndrome in 22q11DS. In addition to their role in ameliorating psychiatric symptoms, psychiatric medications seem to improve neurocognitive functions in 22q11DS.
1Department of Immunology, Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel.;
Thoughts and emotions, can impact physiology. This connection is evident by the emergence of disease following stress, or recovery in response to placebo treatment. Nevertheless, this fundamental aspect of physiology remains largely unexplored. We have recently shown that activity of the brain’s reward system, which is active during positive emotional states and positive expectations, boosts anti-bacterial immunity. In this talk, I will discuss how brain activity can regulate anti-tumor immunity and the potential implications to cancer therapy. Given the crucial role of the reward system in emotional processes, our findings offer a new mechanistic insight to the association between the patient’s psychological state and cancer progression.
1Department of Immunology, Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel.;
Thoughts and emotions, can impact physiology. This connection is evident by the emergence of disease following stress, or recovery in response to placebo treatment. Nevertheless, this fundamental aspect of physiology remains largely unexplored. We have recently shown that activity of the brain’s reward system, which is active during positive emotional states and positive expectations, boosts anti-bacterial immunity. In this talk, I will discuss how brain activity can regulate anti-tumor immunity and the potential implications to cancer therapy. Given the crucial role of the reward system in emotional processes, our findings offer a new mechanistic insight to the association between the patient’s psychological state and cancer progression.
1Department of Psychology, University of Haifa;
Current literature debates whether a link between contagious yawning and the human mirror neuron system (hMNS) exists. The use of transcranial direct current stimulation (tDCS) to elicit changes in yawn contagion during observation of yawns is one way of examining this issue. Research shows that the right inferior frontal gyrus (rIFG) is a core region of the hMNS and its activation is consistently implicated in emotional contagion and recognition. Evidence regarding the rIFG involvement in contagious yawning has been inconclusive hitherto. Thus, this study set to further elucidate the matter. In our study, participants were presented with four types of videos depicting yawning faces, laughing faces, neutral faces and a non-namable facial movement. The study included a pilot which verified the validity of the videos and the experiment during which participants underwent two tDCS conditions: excitation of the right IFG and sham (literature suggests inhibition to be unreliable in this method). The participants' responses were recorded on video during the sessions and later analyzed. We hypothesized that anodal stimulation will increase yawn occurrence and decrease latency time in the participants compared to the sham condition. Results show a significant decrease in latency time, albeit no difference in the amount of yawns. An increase in the temporal proximity could be interpreted as greater affinity towards another. This could mean that the rIFG is specifically involved in a faster reaction time towards another person which in turn increases the yawn contagion impact. The aim of this study is to expand our knowledge of the neural mechanism underpinning contagious yawning and to possibly reveal a new target for screening and treatment in conditions where emotional contagion is impaired (e.g., autism spectrum disorder, post-traumatic stress disorder, psychopaths and schizophrenia).
1The Academic College of Tel-Aviv – Yaffo; 2The Academic College of Tel-Aviv – Yaffo; 3the open university of isreal; 4tel aviv university;
Reversal of age-related cognitive impairments in mice by an extremely low dose of tetrahydrocannabinol Gali breuer3 ,Lital Rachmany1, Efrat Sasson1, Ravid Doron2,3 and Yosef Sarne1. 1Tel Aviv University School of Medicine and 2The Academic College of Tel Aviv-Jaffa and 3The Open University, Israel We have previously shown that an ultra-low dose of THC (delta-9 tetrahydrocannabinol) protected the mice brain from a variety of insults (Ref. 1, 2, 3). A single injection of 0.002 mg/kg of THC (3-4 orders of magnitudes lower than doses that induce the conventional cannabinoid effects in mice) prevented the cognitive damage that was induced by either hypoxia, deep anesthesia, MDMA-toxicity, epileptic seizures or neuroinflammation. THC was applied either 1-7 days before or 1-7 days after the insult, thus providing a wide therapeutic time-window. The protective effect of the single injection of ultra-low THC lasted for at least 7 weeks. The protective effect of THC was accompanied by a long-lasting elevation in pERK, pCREB and BDNF in the hippocampus and frontal cortex of the THC-treated mice. In the present study we tested whether the same ultra-low dose of THC reverses age-dependent cognitive decline in mice. Old (18-24 months) mice performed significantly worse than young (3-4 months) mice in a battery of cognitive assays, including Morris Water Maze, Passive Avoidance, Y maze, Object Recognition and Place Recognition tests. Old mice that had been injected once with 0.002 mg/kg THC performed significantly better than vehicle-treated old mice, and performed similar to naive young mice in all the assays. The improvement in cognitive functioning lasted for at least 7 weeks following a single injection of ultra-low THC. Sirtuin 1 (SIRT1) is an NAD-dependent protein deacetylase that has been previously shown to be involved in neuroprotection and neuroplasticity. It was found to mediate the protective effects of resveratrol, of melatonin and of caloric restriction, and was suggested to take part in the pathology of various neurodegenerative diseases. In the current study we found that a single injection of 0.002 mg/kg THC elevated the amount of SIRT1-immunoreactive proteins in the hippocampus, the frontal cortex and the cerebellum of old mice for at least 7 weeks. We further hypothesized that such long-lasting behavioral and biochemical changes might be accompanied by structural changes in the brain. Indeed, MRI (Magnetic Resonance Imaging) revealed structural alterations in the brains of old mice 5 weeks after the injection of 0.002 mg/kg THC: Diffusion Tensor Imaging (DTI) detected a lower mean diffusivity, indicating higher tissue density in various brain regions including the entorhinal cortex, amygdala, cingulate cortex and caudate/putamen. T2 relaxation images demonstrated a larger volume of 3 regions (entorhinal cortex, prefrontal cortex and posterior hippocampus) in brains of THC-treated old mice. These findings suggest that extremely low doses of THC, that devoid any psychotropic effect and do not induce desensitization, may provide a safe and effective treatment for mild cognitive impairments in ageing humans. References: (1) Behav. Brain Res. 220, 194 (2011); (2) Exp. Brain Res. 221, 437 (2012); (3) J. Neurosci. Res. 92, 1669 (2014)
1The Institute for the Study of Affective Neuroscience, University of Haifa, Israel; 2Department of Psychology, University of Haifa, Israel; 3Neurobiology and Etiology Department, University of Haifa, Israel; 4School of Education, Bar- Ilan University, Israel; 5Gonda Multidisciplinary Brain Research Center, Bar- Ilan University, Israel;
Neuroimaging and behavioral studies have shown that highly exposed first responders display impairment in hippocampal related functions. In a previous study conducted in our lab we found different types of impairments among firefighters and Criminal Scene Investigators (CSI) policemen. Specifically, firefighters struggled to learn that a previously negative context is later associated with a positive outcome, whereas CSI policemen showed a selective impairment in reversing the outcome of a negative cue. A possible explanation for these differences may relate to the frequent traumatic exposure in these populations together with their unique training. Specifically, while firefighters are trained to attend the context during traumatic events, CSI police are trained to attend specific objects in the environment. Alternatively, it is possible that the different impairments are due to job selection that may be influenced by cognitive style. To test these alternative explanations 82 civilian participants were exposed to traumatic/natural pictures, trained to attend cue/context and completed a cue-context reversal paradigm. Finally they were assessed on a performance based paradigm to determine their cognitive style (global/analytic). The results revealed a significant influence of training and cognitive style on performance. Specifically, exposure to traumatic pictures together with cue related training made the participants more vulnerable in that very same aspect. In contrast, after natural-cue- related training participants became more vulnerable in aspects of context and global perception. Furthermore, we found a correlation between cognitive style and performance after exposure to trauma. Thus, participants with a more global perception had greater impairments in reversing the outcome of a negative context.
1Psychology Department, University of Haifa; 2Psychology Department, Tel-Hai College, Israel;
Even when the brain is devoid of external input, complex and intriguing activation patterns emerge. These patterns, also known as the brain's 'resting-state', could be measured with Electroencephalogram (EEG). Introspection, self-referential thoughts and emotional processing which are linked to resting state activity makes it a matter of great interest for developmental research. While there are numerous studies examining resting-state EEG activity in healthy youth, to the best of our knowledge, data on resting-state EEG activity among young anxious populations is sparse. The current study compared spontaneous resting-state EEG activity in healthy and anxious youth. Forty young subjects (Age: 11.08±2.29 years, 18 females, 20 clinically anxious) completed a resting state EEG task. The task consists of two 4 min blocks (2min eyes-open (EO) and 2min eyes-closed (EC)), with each change signaled by a brief 1000Hz (60dB) tone. Data were acquired with a 32-ch Biosemi ActiveTwo system and digitized at a 512Hz sampling rate. Electrodes mounted according to the 10/20 system. Data were offline referenced to the average of all electrodes. After filtering and further artifact rejection, remaining segments (EO/EC) were collapsed for analysis. Statistics were performed on the whole scalp EEG frequencies field power by repeated measure ANOVA and paired t-test. During EO, healthy youth showed increased Beta activity compared to anxious subjects. During EC, significant differences were found between the groups across all frequencies (delta, alpha & beta) except for the theta frequency. Only in healthy youth, a significant reduction in Delta activity was observed during EC compared to EO. Interestingly, both groups exhibited significant changes in Alpha activity during phase transitions but in opposite directions. An increased Alpha activity was found in healthy youth and a decreased Alpha activity observed in the anxious youth.
1Department of Psychology, University of Haifa; 2The Institute of Information Processing and Decision Making (IIPDM) ;
In the current study we aim to explore whether a co-actor's group membership will influence the social inhibition of return (SIOR; Welsh et al., 2005). SIOR refers to slower reaction time (RTs) toward a location already searched, whether the search had been done by the individual or by another co-actor. In the basic paradigm two participants perform the task together, sitting in front of a computer screen, facing each other. Each participant, in turn, responds to a peripherally presented target in two successive trials. The first trial is performed after the other participant's response and is aimed at examining SIOR. The second trial for each participant is aimed at studying the self-induced IOR. In order to examine how group membership affects SIOR, in the present study we recruited Muslim and Jewish students to perform the task either with an in-group member or with an out-group member. Based on a theory according to which IOR is a foraging facilitator (Klein, 2000), we predicted that SIOR would be larger when performing the task with an in-group member than with an out-group member. The results confirmed our prediction and thus strengthened the notion regarding the sociality of the SIOR effect by indicating that the co-actor's group affiliation modulates the effect. This finding also opens the possibility that SIOR could be used, in the future, as an indicator of the quality of relationships.
1Dept. of Behavioral Science, Ariel University Israel; 2Institute of Psychology, Eötvös Loránd University, Budapest, Hungary; 3Semmelweis University - Faculty of Health Sciences, Budapest, Hungary; 4Nyírő Gyula Hospital - National Institute of Psychiatry and Addictions Budapest, Hungary; 5Division of Enforcement and Inspection, Ministry of Health, Jerusalem, Israel; 6Department for the Treatment of Substance Abuse, Ministry of Health, Jerusalem, Israel;
There is a growing use of novel psychoactive substances (NPSs) including synthetic cannabinoids. Synthetic cannabinoid products have effects similar to those of natural cannabis but are more potent and dangerous and their use has resulted in various adverse effects. The purpose of the study was to assess whether persistent use of synthetic cannabinoids (SCs) is associated with impairments of executive function in regular SC users. A total of 38 synthetic cannabinoids users, 43 recreational cannabis users, and 41 non-users were studied in Hungary and Israel. Computerized cognitive function tests, the classic Stroop Word-Color naming task, n-back task, and a free-recall memory task were used. Synthetic cannabinoid users performed significantly worse than both recreational cannabis users and non-cannabis users on working-memory (less accuracy in the n-back task), attention (overall slow responses and more errors in the Stroop task) and long-term memory (less word recall in free recall task). Additionally, they have also shown higher ratings of depression compared with both recreational users and non-users. This may have major implications for our understanding of the long-term consequences of chronic use of SCs.
1Sagol Department of Neurobiology; 2Institution for Information Processing and Decision Making, University of Haifa, Israel;
Narratives serve as a fundamental component of human consciousness, culture, and memory. The ability to produce a coherent story is found to be a sign of a mature and healthy personality. The absence of the ability to produce coherent narratives has been correlated with severe mental illness and trauma. Despite a growing appreciation that naturalistic, time-propagating stimuli are highly useful in illuminating various cognitive faculties, the mechanisms that support the extraction of narrative from such complex stimuli are largely unknown. We aim at bridging this gap by unearthing the neural structures and networks that underpin narrative comprehension and formation. We devised a novel experimental design, wherein two groups are presented with movie scenes (semi-naturalistic), which differ only in the narrative context in which the scenes are embedded, integrating both literary and philosophical-psychological definitions of narrative. Using standard and advanced fMRI analysis techniques, we seek to detect the neural mechanisms that support narrative formation. Functional connectivity fMRI results indicate specific brain regions to be imperative in narrative construction, situated in the precuneus and limbic (hippocampus, amygdala) regions, the para-cingulate (morphologically different in schizophrenia) area and the lingual gyrus (associated with analysis of logical conditions and encoding of visual memories). We hope that achieving a better understanding of the neural underpinning of narrative formation will potentially benefit both basic brain research as well as the clinical field, which emphasizes the pivotal importance of narrative to human experience and mental resilience. Characterizing the underlying processes of narrative formation may hopefully be harnessed to devise novel clinical interventions in populations that are impaired in this basic feature.
1Institute of Information Processing and Decision Making, Haifa University; 2Department of Human Biology, Faculty of Science & Science Education; 3Edmond J. Safra Brain Research Center for the Study of Learning Disabilities;
Covert and overt speech production were investigated using a repetition task that aimed to test the effects of input modality. According to the Wernicke-Geschwind model, sensory systems participate in speech production. Initial visual and auditory language stimuli are processed in their respective primary and secondary cortical sensory areas and integrated in the angular gyrus, and from that point, visual and auditory linguistic stimuli are processed by the same mechanisms. The SFC model suggested by Hickok, Houde, and Rong (2011) posits that speech generation involves predictions of sensory consequences to inner sensory representations of the vocal target to be conveyed, based on the state of the vocal muscles. The model assumes that most of speech output is based on inner representations of sensory targets. However, if an auditory stimulus is to be repeated, these inner representations may be not be necessary. Based on these models, auditory sensory input targets were hypothesized to result in differential output patterns compared to visual sensory targets in both response duration measurements and surface electromyography (EMG) measurements of Orbicularis Oris Inferior and Thyrohyoideus muscles. Results revealed that sentence repetition duration was longer in the auditory input condition compared to visual input conditions. Additionally, mean of EMG activity (µV) measured during sentence presentation reveal inhibitory innervation as a function of the output condition. An interaction was revealed during sentence presentation, so that in covert speech production only auditory input elicited a significant inhibitory response, while in overt speech production both auditory and visual input targets elicited significant inhibitory responses. The
1 Department of Psychology and the Institute of Information Processing and Decision Making, University of Haifa, Israel.;
Background and aim: Literature has long emphasized the involvement of cortical and sub-cortical mechanisms